New generation regulatable fusogenic oncolytic herpes simplex virus type 1 virus and methods of use

ABSTRACT

Malignant tumors that are resistant to conventional therapies represent significant therapeutic challenges. An embodiment of the present invention provides a new generation regulatable fusogenic oncolytic herpes simplex virus-1 that is more effective at selective killing target cells, such as tumor cells. In various embodiments presented herein, the oncolytic virus described herein is suitable for treatment of solid tumors, as well as other cancers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 62/772,293 filed Nov. 28, 2018, the contentsof which is incorporated herein by reference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Nov. 8, 2019, isnamed 043214-090140WOPT_SL.txt and is 204,542 bytes in size.

FIELD OF INVENTION

The present invention is directed compositions and methods of treatingcancer using regulatable fusogenic oncolytic herpes simplex virus 1(HSV-1) virus.

BACKGROUND

Oncolytic viral therapy entails harnessing the ability of a virus toreproduce in and lyse human cells and directing this viralreplication-dependent lysis preferentially toward cancerous cells.Advances in cancer biology, together with a detailed understanding ofthe roles of host factors and virus-encoded gene products in controllingvirus production in infected cells, have facilitated the use of someviruses as potential therapeutic agents against cancer (Aghi andMartuza, 2005; Parato et al., 2005). Herpes simplex virus (HSV)possesses several unique properties as an oncolytic agent (Aghi andMartuza, 2005). It can infect a broad range of cell types, leading tothe replication of new virus and cell death. HSV has a short replicationcycle (9 to 18 h) and encodes many non-essential genes that, whendeleted, greatly restrict the ability of the virus to replicate innon-dividing normal cells. Because of its large genome, multipletherapeutic genes can be packaged into the genome of oncolyticrecombinants.

The use of a replication-conditional strain of HSV-1 as an oncolyticagent was first reported for the treatment of malignant gliomas (Martuzaet al., 1991). Since then, various efforts have been made in an attemptto broaden their therapeutic efficacy and increase the replicationspecificity of the virus in tumor cells. Not surprisingly, however,deletion of genes that impair viral replication in normal cells alsoleads to a marked decrease in the oncolytic activity of the virus forthe targeted tumor cells (Advani et al., 1998; Chung et al., 1999).Currently, no oncolytic viruses that are able to kill only tumor cellswhile leaving normal cells intact are available. Consequently, thetherapeutic doses of existing oncolytic viruses are significantlyrestricted (Aghi and Martuza, 2005). The availability of an oncolyticvirus whose replication can be tightly controlled and adjustedpharmacologically would offer greatly increased safety and therapeuticefficacy. Such a regulatable oncolytic virus would minimize unwantedreplication in adjacent and distant tissues as well as undesirableprogeny virus overload in the target area after the tumor has beeneliminated. This regulatory feature would also allow the oncolyticactivity of the virus to be quickly shut down should adverse effects bedetected (Aghi and Martuza, 2005; Shen and Nemunaitis, 2005). Workdescribed herein presents a new generation of regulatable fusogenicvariant of an oncolytic HSV that is significantly more effective atkilling cancer cells than other oncolytic HSV viruses.

SUMMARY OF THE INVENTION

This invention described herein is a novel tetracycline-regulatableHSV-1 ICP0 null mutant based fusogenic oncolytic virus, QREO5-F, whosepreferential replication ability in human cancer cells over normal cellsis further enhanced through series propagation of virus in human cancercell lines. It is shown herein that infection of multiple human cancercell types that include breast cancer, liver cancer, melanoma,pancreatic cancer, ovarian cancer, and several different non-small celllung cancer cells with QREO5-F lead to 36,000-to 5×10⁷-foldtetracycline-dependent progeny virus production, while little viralreplication and virus-associated cytotoxicity are observed in infectedgrowing as well as growth-arrested normal human fibroblasts. QREO5-F is,thus, a replication-competent oncolytic virus in the presence oftetracycline/doxycycline, and a replication-defective virus in theabsence of tetracycline/doxycycline.

Importantly, QREO5-F is highly effective against pre-established CT26.WTcolon carcinoma tumor in immune-competent mice. QREO5-F virotherapy ledto induction of effective tumor-specific immunity that can prevent thetumor growth following re-challenge with the same type of tumor cells.Collectively, QREO5-F is an excellent candidate with efficacy and safetyfeatures suitable for clinical development.

Accordingly, one aspect described herein provides an oncolytic HerpesSimplex Virus (HSV) comprising recombinant DNA, wherein the recombinantDNA comprises: a gene comprising a 5′ untranslated region and a HSV-1,or HSV-2, VP5 gene that is operably linked to an VP5 promoter comprisinga TATA element; a tetracycline operator sequence positioned between 6and 24 nucleotides 3′ to said TATA element, wherein the VP5 gene lies 3′to said tetracycline operator sequence; a gene sequence encodingtetracycline repressor operably linked to an HSV immediate-earlypromoter, wherein the gene sequence is located at the ICP0 locus; avariant gene that increases syncytium formation as compared to wildtype, wherein the HSV-1, or HSV-2, variant gene is selected from thegroup consisting of: a glycoprotein K (gK) variant; a glycoprotein B(gB) variant; a UL24 variant; and UL20 gene variant; and a gene sequenceencoding a functional ICP34.5 protein, wherein said oncolytic HSV doesnot encode functional ICP0 and does not contain a ribozyme sequencelocated in said 5′ untranslated region of VP5.

In one embodiment of any aspect, the variant gene is a gK variant genethat encodes an amino acid substitution selected from the groupconsisting of: an Ala to Thr amino acid substitution corresponding toamino acid 40 of SEQ ID NO: 2; an Ala to “x” amino acid substitutioncorresponding to amino acid 40 of SEQ ID NO: 2, wherein “x” is any aminoacid; an Asp to Asn amino acid substitution corresponding to amino acid99 of SEQ ID NO: 2; a Leu to Pro amino acid substitution correspondingto amino acid 304 of SEQ ID NO: 2; and an Arg to Leu amino acidsubstitution corresponding to amino acid 310 of SEQ ID NO: 2.

In one embodiment of any aspect, the tetracycline operator sequencecomprises two Op2 repressor binding sites.

In one embodiment of any aspect, the VP5 promoter is an HSV-1 or HSV-2VP5 promoter.

In one embodiment of any aspect, the HSV immediate-early promoter is anHSV-1 or HSV-2 immediate-early promoter or the HCMV immediate-earlypromoter.

In one embodiment of any aspect, the HSV immediate-early promoter isselected from the group consisting of: ICP0 promoter, ICP4 promoter,ICP27 promoter, and ICP22 promoter.

In one embodiment of any aspect, the recombinant DNA is part of theHSV-1 genome. In one embodiment of any aspect, the recombinant DNA ispart of the HSV-2 genome.

In one embodiment of any aspect, the oncolytic HSV described hereinfurther comprises a pharmaceutically acceptable carrier

In one embodiment of any aspect, the oncolytic HSV described hereinfurther encodes at least one polypeptide that can increase the efficacyof the oncolytic HSV to induce an anti-tumor-specific immunity. In oneembodiment, the at least one polypeptide encodes a product selected fromthe group consisting of: interleukin 2 (IL2), interleukin 12 (IL12),interleukin 15 (IL15), an anti-PD-1 antibody or antibody reagent, ananti-PD-L1 antibody or antibody reagent, an anti-OX40 antibody orantibody reagent, a CTLA-4 antibody or antibody reagent, a TIM-3antibody or antibody reagent, a TIGIT antibody or antibody reagent, asoluble interleukin 10 receptor (IL10R), a fusion polypeptide between asoluble IL10R and IgG-Fc domain, a soluble TGFβ type II receptor(TGFBRII), a fusion polypeptide between a soluble TGFBRII and IgG-Fcdomain, an anti-IL10R antibody or antibody reagent, an anti-IL10antibody or antibody reagent, an anti-TGF-β1 antibody or antibodyreagent, and an anti-TGFBRII antibody or antibody reagent.

In one embodiment of any aspect, the oncolytic HSV described hereinfurther encodes fusogenic activity.

Another aspect described herein provides a composition comprising any ofthe oncolytic HSV described herein. In one embodiment, the compositionfurther comprises a pharmaceutically acceptable carrier.

Another aspect described herein provides a method for treating cancercomprising administering any of the oncolytic HSV described herein or acomposition thereof to a subject having cancer.

In one embodiment of any aspect, the cancer is a solid tumor.

In one embodiment of any aspect, the tumor is benign or malignant.

In one embodiment of any aspect, the subject is diagnosed or has beendiagnosed as having a carcinoma, a melanoma, a sarcoma, a germ celltumor, or a blastoma. In one embodiment of any aspect, the subject isdiagnosed or has been diagnosed as having non-small-cell lung cancer,breast cancer, brain cancer, colon cancer, prostate cancer, livercancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer,kidney cancer, and pancreatic cancer.

In one embodiment of any aspect, the cancer is metastatic.

In one embodiment of any aspect, the oncolytic HSV is administeredlocally, regionally, or systemically. In one embodiment of aspect, theoncolytic HSV is administered directly to the tumor. In one embodimentof any aspect, the regional administration is the hepatic arteryinfusion, renal artery infusion, or the pulmonary infusion. In oneembodiment of any aspect, the systemic administration is the intravenousinfusion.

In one embodiment of any aspect, the method further comprisesadministering an agent that regulates the tet operator. In oneembodiment, the agent is doxycycline or tetracycline. In one embodimentof any aspect, the agent is administered locally or systemically. In oneembodiment of any aspect, the systemic administration is oraladministration.

Another aspect described herein provides an oncolytic Herpes SimplexVirus (HSV) comprising recombinant DNA, wherein the recombinant DNA doesnot encode functional ICP0 and encodes fusogenic activity.

Definitions

All references cited herein are incorporated by reference in theirentirety as though fully set forth.

Unless otherwise defined herein, scientific and technical terms used inconnection with the present application shall have the meanings that arecommonly understood by those of ordinary skill in the art to which thisdisclosure belongs. It should be understood that this invention is notlimited to the particular methodology, protocols, and reagents, etc.,described herein and as such can vary. Definitions of common terms canbe found in Singleton et al., Dictionary of Microbiology and MolecularBiology 3^(rd) ed., J. Wiley & Sons New York, N.Y. (2001); March,Advanced Organic Chemistry Reactions, Mechanisms and Structure 5^(th)ed., J. Wiley & Sons New York, N.Y. (2001); Michael Richard Green andJoseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012);Davis et al., Basic Methods in Molecular Biology, Elsevier SciencePublishing, Inc., New York, USA (2012); Jon Lorsch (ed.) LaboratoryMethods in Enzymology: DNA, Elsevier, (2013); Frederick M. Ausubel(ed.), Current Protocols in Molecular Biology (CPMB), John Wiley andSons, (2014); John E. Coligan (ed.), Current Protocols in ProteinScience (CPPS), John Wiley and Sons, Inc., (2005); and Ethan M Shevach,Warren Strobe, (eds.) Current Protocols in Immunology (CPI) (John E.Coligan, ADA M Kruisbeek, David H Margulies, John Wiley and Sons, Inc.,(2003); each of which provide one skilled in the art with a generalguide to many of the terms used in the present application.

As used herein, a “subject” means a human or animal. Usually the animalis a vertebrate such as a primate, rodent, domestic animal or gameanimal. Primates include, for example, chimpanzees, cynomologousmonkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include,for example, mice, rats, woodchucks, ferrets, rabbits and hamsters.Domestic and game animals include, for example, cows, horses, pigs,deer, bison, buffalo, feline species, e.g., domestic cat, caninespecies, e.g., dog, fox, wolf, avian species, e.g., chicken, emu,ostrich, and fish, e.g., trout, catfish and salmon. In some embodiments,the subject is a mammal, e.g., a primate, e.g., a human. The terms,“individual,” “patient” and “subject” are used interchangeably herein.

Preferably, the subject is a mammal. The mammal can be a human,non-human primate, mouse, rat, dog, cat, horse, or cow, but is notlimited to these examples. Mammals other than humans can beadvantageously used as subjects that represent animal models of diseasee.g., cancer. A subject can be male or female.

A subject can be one who has been previously diagnosed with oridentified as suffering from or having a condition in need of treatment(e.g. cancer) or one or more complications related to such a condition,and optionally, have already undergone treatment for the condition orthe one or more complications related to the condition. Alternatively, asubject can also be one who has not been previously diagnosed as havingsuch condition or related complications. For example, a subject can beone who exhibits one or more risk factors for the condition or one ormore complications related to the condition or a subject who does notexhibit risk factors.

As used herein, the terms “treat,” “treatment,” “treating,” or“amelioration” refer to therapeutic treatments, wherein the object is toreverse, alleviate, ameliorate, inhibit, slow down or stop theprogression or severity of a condition associated with a disease ordisorder, e.g. cancer. The term “treating” includes reducing oralleviating at least one adverse effect or symptom of a condition,disease or disorder. Treatment is generally “effective” if one or moresymptoms or clinical markers are reduced. Alternatively, treatment is“effective” if the progression of a disease is reduced or halted. Thatis, “treatment” includes not just the improvement of symptoms ormarkers, but also a cessation of, or at least slowing of, progress orworsening of symptoms compared to what would be expected in the absenceof treatment. Beneficial or desired clinical results include, but arenot limited to, alleviation of one or more symptom(s), diminishment ofextent of disease, stabilized (i.e., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state, remission (whether partial or total), and/ordecreased mortality, whether detectable or undetectable. The term“treatment” of a disease also includes providing relief from thesymptoms or side-effects of the disease (including palliativetreatment).

In the various embodiments described herein, it is further contemplatedthat variants (naturally occurring or otherwise), alleles, homologs,conservatively modified variants, and/or conservative substitutionvariants of any of the particular polypeptides described areencompassed. As to amino acid sequences, one of ordinary skill willrecognize that individual substitutions, deletions or additions to anucleic acid, peptide, polypeptide, or protein sequence which alters asingle amino acid or a small percentage of amino acids in the encodedsequence is a “conservatively modified variant” where the alterationresults in the substitution of an amino acid with a chemically similaramino acid and retains the desired activity of the polypeptide. Suchconservatively modified variants are in addition to and do not excludepolymorphic variants, interspecies homologs, and alleles consistent withthe disclosure.

A given amino acid can be replaced by a residue having similarphysiochemical characteristics, e.g., substituting one aliphatic residuefor another (such as Ile, Val, Leu, or Ala for one another), orsubstitution of one polar residue for another (such as between Lys andArg; Glu and Asp; or Gln and Asn). Other such conservativesubstitutions, e.g., substitutions of entire regions having similarhydrophobicity characteristics, are well known. Polypeptides comprisingconservative amino acid substitutions can be tested in any one of theassays described herein to confirm that a desired activity, e.g.ligan-mediated receptor activity and specificity of a native orreference polypeptide is retained.

Amino acids can be grouped according to similarities in the propertiesof their side chains (in A. L. Lehninger, in Biochemistry, second ed.,pp. 73-75, Worth Publishers, New York (1975)): (1) non-polar: Ala (A),Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M); (2)uncharged polar: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N),Gln (Q); (3) acidic: Asp (D), Glu (E); (4) basic: Lys (K), Arg (R), His(H). Alternatively, naturally occurring residues can be divided intogroups based on common side-chain properties: (1) hydrophobic:Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser,Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5)residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp,Tyr, Phe. Non-conservative substitutions will entail exchanging a memberof one of these classes for another class. Particular conservativesubstitutions include, for example; Ala into Gly or into Ser; Arg intoLys; Asn into Gln or into His; Asp into Glu; Cys into Ser; Gln into Asn;Glu into Asp; Gly into Ala or into Pro; His into Asn or into Gln; Ileinto Leu or into Val; Leu into Ile or into Val; Lys into Arg, into Glnor into Glu; Met into Leu, into Tyr or into Ile; Phe into Met, into Leuor into Tyr; Ser into Thr; Thr into Ser; Trp into Tyr; Tyr into Trp;and/or Phe into Val, into Ile or into Leu.

In some embodiments, a polypeptide described herein (or a nucleic acidencoding such a polypeptide) can be a functional fragment of one of theamino acid sequences described herein. As used herein, a “functionalfragment” is a fragment or segment of a peptide which retains at least50% of the wildtype reference polypeptide's activity according to anassay known in the art or described below herein. A functional fragmentcan comprise conservative substitutions of the sequences disclosedherein.

In some embodiments, a polypeptide described herein can be a variant ofa polypeptide or molecule as described herein. In some embodiments, thevariant is a conservatively modified variant. Conservative substitutionvariants can be obtained by mutations of native nucleotide sequences,for example. A “variant,” as referred to herein, is a polypeptidesubstantially homologous to a native or reference polypeptide, but whichhas an amino acid sequence different from that of the native orreference polypeptide because of one or a plurality of deletions,insertions or substitutions. Variant polypeptide-encoding DNA sequencesencompass sequences that comprise one or more additions, deletions, orsubstitutions of nucleotides when compared to a native or reference DNAsequence, but that encode a variant protein or fragment thereof thatretains activity of the non-variant polypeptide. A wide variety ofPCR-based site-specific mutagenesis approaches are known in the art andcan be applied by the ordinarily skilled artisan.

A variant amino acid or DNA sequence can be at least 90%, at least 91%,at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or more, identical to a native orreference sequence. The degree of homology (percent identity) between anative and a mutant sequence can be determined, for example, bycomparing the two sequences using freely available computer programscommonly employed for this purpose on the world wide web (e.g. BLASTp orBLASTn with default settings).

Alterations of the native amino acid sequence can be accomplished by anyof a number of techniques known to one of skill in the art. Mutationscan be introduced, for example, at particular loci by synthesizingoligonucleotides containing a mutant sequence, flanked by restrictionsites permitting ligation to fragments of the native sequence. Followingligation, the resulting reconstructed sequence encodes an analog havingthe desired amino acid insertion, substitution, or deletion.Alternatively, oligonucleotide-directed site-specific mutagenesisprocedures can be employed to provide an altered nucleotide sequencehaving particular codons altered according to the substitution,deletion, or insertion required. Techniques for making such alterationsare well established and include, for example, those disclosed by Walderet al. (Gene 42:133, 1986); Bauer et al. (Gene 37:73, 1985); Craik(BioTechniques, January 1985, 12-19); Smith et al. (Genetic Engineering:Principles and Methods, Plenum Press, 1981); and U.S. Pat. Nos.4,518,584 and 4,737,462, which are herein incorporated by reference intheir entireties. Any cysteine residue not involved in maintaining theproper conformation of a polypeptide also can be substituted, generallywith serine, to improve the oxidative stability of the molecule andprevent aberrant crosslinking. Conversely, cysteine bond(s) can be addedto a polypeptide to improve its stability or facilitate oligomerization.

As used herein, the term “DNA” is defined as deoxyribonucleic acid. Theterm “polynucleotide” is used herein interchangeably with “nucleic acid”to indicate a polymer of nucleosides. Typically, a polynucleotide iscomposed of nucleosides that are naturally found in DNA or RNA (e.g.,adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine,deoxythymidine, deoxyguanosine, and deoxycytidine) joined byphosphodiester bonds. However, the term encompasses molecules comprisingnucleosides or nucleoside analogs containing chemically or biologicallymodified bases, modified backbones, etc., whether or not found innaturally occurring nucleic acids, and such molecules may be preferredfor certain applications. Where this application refers to apolynucleotide it is understood that both DNA, RNA, and in each caseboth single- and double-stranded forms (and complements of eachsingle-stranded molecule) are provided. “Polynucleotide sequence” asused herein can refer to the polynucleotide material itself and/or tothe sequence information (i.e. the succession of letters used asabbreviations for bases) that biochemically characterizes a specificnucleic acid. A polynucleotide sequence presented herein is presented ina 5′ to 3′ direction unless otherwise indicated.

The term “operably linked,” as used herein, refers to the arrangement ofvarious nucleic acid molecule elements relative to each other such thatthe elements are functionally connected and are able to interact witheach other. Such elements may include, without limitation, a promoter,an enhancer, a polyadenylation sequence, one or more introns and/orexons, and a coding sequence of a gene of interest to be expressed. Thenucleic acid sequence elements, when operably linked, can act togetherto modulate the activity of one another, and ultimately may affect thelevel of expression of the gene of interest, including any of thoseencoded by the sequences described above.

The term “vector,” as used herein, refers to a carrier nucleic acidmolecule into which a nucleic acid sequence can be inserted forintroduction into a cell where it can be replicated. A nucleic acidsequence can be “exogenous,” which means that it is foreign to the cellinto which the vector is being introduced or that the sequence ishomologous to a sequence in the cell but in a position within the hostcell nucleic acid in which the sequence is ordinarily not found. Vectorsinclude plasmids, cosmids, viruses (bacteriophage, animal viruses, andplant viruses), and artificial chromosomes (e.g., YACs). One of skill inthe art would be well equipped to construct a vector through standardrecombinant techniques (see, for example, Maniatis et al., 1988 andAusubel et al., 1994, both of which are incorporated herein byreference). Additionally, the techniques described herein anddemonstrated in the referenced figures are also instructive with regardto effective vector construction.

The term “oncolytic HSV-1 vector” refers to a genetically engineeredHSV-1 virus corresponding to at least a portion of the genome of HSV-1that is capable of infecting a target cell, replicating, and beingpackaged into HSV-1 virions. The genetically engineered virus comprisesdeletions and or mutations and or insertions of nucleic acid that renderthe virus oncolytic such that the engineered virus replicates in- andkills-tumor cells by oncolytic activity. The virus may be attenuated ornon-attenuated. The virus may or may not deliver a transgene—thatdiffers from the HSV viral genome. In one embodiment, the oncolyticHSV-1 vector does not express a transgene to produce a protein foreignto the virus.

The term “promoter,” as used herein, refers to a nucleic acid sequencethat regulates, either directly or indirectly, the transcription of acorresponding nucleic acid coding sequence to which it is operablylinked. The promoter may function alone to regulate transcription, or,in some cases, may act in concert with one or more other regulatorysequences such as an enhancer or silencer to regulate transcription ofthe gene of interest. The promoter comprises a DNA regulatory sequence,wherein the regulatory sequence is derived from a gene, which is capableof binding RNA polymerase and initiating transcription of a downstream(3′-direction) coding sequence. A promoter generally comprises asequence that functions to position the start site for RNA synthesis.The best-known example of this is the TATA box, but in some promoterslacking a TATA box, such as, for example, the promoter for the mammalianterminal deoxynucleotidyl transferase gene and the promoter for the SV40late genes, a discrete element overlying the start site itself helps tofix the place of initiation. Additional promoter elements regulate thefrequency of transcriptional initiation. Typically, these are located inthe region 30-110 bp upstream of the start site, although a number ofpromoters have been shown to contain functional elements downstream ofthe start site as well. To bring a coding sequence “under the controlof” a promoter, one can position the 5′ end of the transcriptioninitiation site of the transcriptional reading frame “downstream” of(i.e., 3′ of) the chosen promoter. The “upstream” promoter stimulatestranscription of the DNA and promotes expression of the encoded RNA.

The spacing between promoter elements frequently is flexible, so thatpromoter function is preserved when elements are inverted or movedrelative to one another. Depending on the promoter used, individualelements can function either cooperatively or independently to activatetranscription. The promoters described herein may or may not be used inconjunction with an “enhancer,” which refers to a cis-acting regulatorysequence involved in the transcriptional activation of a nucleic acidsequence, such as those for the genes, or portions or functionalequivalents thereof, listed herein.

A promoter may be one naturally associated with a nucleic acid sequence,as may be obtained by isolating the 5′ non-coding sequences locatedupstream of the coding segment and/or exon. Such a promoter can bereferred to as “endogenous.” Similarly, an enhancer may be one naturallyassociated with a nucleic acid sequence, located either downstream orupstream of that sequence. Alternatively, certain advantages may begained by positioning the coding nucleic acid segment under the controlof a recombinant or heterologous promoter, which refers to a promoterthat is not normally associated with a nucleic acid sequence in itsnatural environment. A recombinant or heterologous enhancer refers alsoto an enhancer not normally associated with a nucleic acid sequence inits natural environment. Such promoters or enhancers may includepromoters or enhancers of other genes, and promoters or enhancersisolated from any other virus, or prokaryotic or eukaryotic cell, andpromoters or enhancers not “naturally occurring,” i.e., containingdifferent elements of different transcriptional regulatory regions,and/or mutations that alter expression. For example, promoters that aremost commonly used in recombinant DNA construction include, the HCMVimmediate-early promoter, the beta-lactamase (penicillinase), lactoseand tryptophan (trp) promoter systems.

A “gene,” or a “sequence which encodes” a particular protein, is anucleic acid molecule which is transcribed (in the case of DNA) andtranslated (in the case of mRNA) into a polypeptide in vitro or in vivowhen placed under the control of one or more appropriate regulatorysequences. A gene of interest can include, but is no way limited to,cDNA from eukaryotic mRNA, genomic DNA sequences from eukaryotic DNA,and even synthetic DNA sequences. A transcription termination sequencewill usually be located 3′ to the gene sequence. Typically, apolyadenylation signal is provided to terminate transcription of genesinserted into a recombinant virus.

The term “polypeptide” as used herein refers to a polymer of aminoacids. The terms “protein” and “polypeptide” are used interchangeablyherein. A peptide is a relatively short polypeptide, typically betweenabout 2 and 60 amino acids in length. Polypeptides used herein typicallycontain amino acids such as the 20 L-amino acids that are most commonlyfound in proteins. However, other amino acids and/or amino acid analogsknown in the art can be used. One or more of the amino acids in apolypeptide may be modified, for example, by the addition of a chemicalentity such as a carbohydrate group, a phosphate group, a fatty acidgroup, a linker for conjugation, functionalization, etc. A polypeptidethat has a nonpolypeptide moiety covalently or noncovalently associatedtherewith is still considered a “polypeptide.” Exemplary modificationsinclude glycosylation and palmitoylation. Polypeptides can be purifiedfrom natural sources, produced using recombinant DNA technology orsynthesized through chemical means such as conventional solid phasepeptide synthesis, etc. The term “polypeptide sequence” or “amino acidsequence” as used herein can refer to the polypeptide material itselfand/or to the sequence information (i.e., the succession of letters orthree letter codes used as abbreviations for amino acid names) thatbiochemically characterizes a polypeptide. A polypeptide sequencepresented herein is presented in an N-terminal to C-terminal directionunless otherwise indicated.

The term “transgene” refers to a particular nucleic acid sequenceencoding a polypeptide or a portion of a polypeptide to be expressed ina cell into which the nucleic acid sequence is inserted. The term“transgene” is meant to include (1) a nucleic acid sequence that is notnaturally found in the cell (i.e., a heterologous nucleic acidsequence); (2) a nucleic acid sequence that is a mutant form of anucleic acid sequence naturally found in the cell into which it has beeninserted; (3) a nucleic acid sequence that serves to add additionalcopies of the same (i.e., homologous) or a similar nucleic acid sequencenaturally occurring in the cell into which it has been inserted; or (4)a silent naturally occurring or homologous nucleic acid sequence whoseexpression is induced in the cell into which it has been inserted. A“mutant form” or “modified nucleic acid” or “modified nucleotide”sequence means a sequence that contains one or more nucleotides that aredifferent from the wild-type or naturally occurring sequence, i.e., themutant nucleic acid sequence contains one or more nucleotidesubstitutions, deletions, and/or insertions. In some cases, the gene ofinterest may also include a sequence encoding a leader peptide or signalsequence such that the transgene product may be secreted from the cell.

As used herein, the term “antibody reagent” refers to a polypeptide thatincludes at least one immunoglobulin variable domain or immunoglobulinvariable domain sequence and which specifically binds a given antigen.An antibody reagent can comprise an antibody or a polypeptide comprisingan antigen-binding domain of an antibody. In some embodiments of any ofthe aspects, an antibody reagent can comprise a monoclonal antibody or apolypeptide comprising an antigen-binding domain of a monoclonalantibody. For example, an antibody can include a heavy (H) chainvariable region (abbreviated herein as VH), and a light (L) chainvariable region (abbreviated herein as VL). In another example, anantibody includes two heavy (H) chain variable regions and two light (L)chain variable regions. The term “antibody reagent” encompassesantigen-binding fragments of antibodies (e.g., single chain antibodies,Fab and sFab fragments, F(ab′)2, Fd fragments, Fv fragments, scFv, CDRs,and domain antibody (dAb) fragments (see, e.g. de Wildt et al., Eur J.Immunol. 1996; 26(3):629-39; which is incorporated by reference hereinin its entirety)) as well as complete antibodies. An antibody can havethe structural features of IgA, IgG, IgE, IgD, or IgM (as well assubtypes and combinations thereof). Antibodies can be from any source,including mouse, rabbit, pig, rat, and primate (human and non-humanprimate) and primatized antibodies. Antibodies also include midibodies,nanobodies, humanized antibodies, chimeric antibodies, and the like.

The term “oncolytic activity,” as used herein, refers to cytotoxiceffects in vitro and/or in vivo exerted on tumor cells without anyappreciable or significant deleterious effects to normal cells under thesame conditions. The cytotoxic effects under in vitro conditions aredetected by various means as known in prior art, for example, bystaining with a selective stain for dead cells, by inhibition of DNAsynthesis, or by apoptosis. Detection of the cytotoxic effects under invivo conditions is performed by methods known in the art.

A “biologically active” portion of a molecule, as used herein, refers toa portion of a larger molecule that can perform a similar function asthe larger molecule. Merely by way of non-limiting example, abiologically active portion of a promoter is any portion of a promoterthat retains the ability to influence gene expression, even if onlyslightly. Similarly, a biologically active portion of a protein is anyportion of a protein which retains the ability to perform one or morebiological functions of the full-length protein (e.g. binding withanother molecule, phosphorylation, etc.), even if only slightly.

As used herein, the term “administering,” refers to the placement of atherapeutic or pharmaceutical composition as disclosed herein into asubject by a method or route which results in at least partial deliveryof the agent at a desired site. Pharmaceutical compositions comprisingagents as disclosed herein can be administered by any appropriate routewhich results in an effective treatment in the subject.

The term “statistically significant” or “significantly” refers tostatistical significance and generally means a two standard deviation(2SD) or greater difference.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients or reaction conditions usedherein should be understood as modified in all instances by the term“about.” The term “about” when used in connection with percentages canmean±1%.

As used herein, the term “comprising” means that other elements can alsobe present in addition to the defined elements presented. The use of“comprising” indicates inclusion rather than limitation. The term“consisting of” refers to compositions, methods, and respectivecomponents thereof as described herein, which are exclusive of anyelement not recited in that description of the embodiment. As usedherein the term “consisting essentially of” refers to those elementsrequired for a given embodiment. The term permits the presence ofadditional elements that do not materially affect the basic and novel orfunctional characteristic(s) of that embodiment of the technology.

The singular terms “a,” “an,” and “the” include plural referents unlesscontext clearly indicates otherwise. Similarly, the word “or” isintended to include “and” unless the context clearly indicatesotherwise. Although methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of thisdisclosure, suitable methods and materials are described below. Theabbreviation, “e.g.” is derived from the Latin exempli gratia, and isused herein to indicate a non-limiting example. Thus, the abbreviation“e.g.” is synonymous with the term “for example.”

In some embodiments, the numbers expressing quantities of ingredients,properties such as molecular weight, reaction conditions, and so forth,used to describe and claim certain embodiments of the application are tobe understood as being modified in some instances by the term “about.”Accordingly, in some embodiments, the numerical parameters set forth inthe written description and attached claims are approximations that canvary depending upon the desired properties sought to be obtained by aparticular embodiment. In some embodiments, the numerical parametersshould be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and parameters setting forth the broad scopeof some embodiments of the application are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspracticable.

With the aforementioned preliminary descriptions and definitions inmind, additional background is provided herein below to provide contextfor the genesis and development of the inventive vectors, compositionsand methods described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments are illustrated in the referenced figures. It isintended that the embodiments and figures disclosed herein are to beconsidered illustrative rather than restrictive.

FIG. 1 shows a schematic diagram of the genome of HSV-1 recombinantQREO5. UL and US represent the unique long and unique short regions ofthe HSV-1 genome, respectively, which are flanked by their correspondinginverted repeat regions (open boxes). The replacement of the ICP0 codingsequences with DNA sequences encoding tetR (black box) and intron II ofthe rabbit β-globin gene (vertical line box) flanked by ICP0 sequencesare shown above the diagram of the HSV-1 genome. An expanded DNAfragment containing the ICP5 open reading frame (grey box) under thecontrol of the tetO-bearing HSV-1 ICP5 promoter (cross-hatched box).

FIGS. 2A and 2B show QREO5 replicates significantly more efficientlythan KTR27 in Vero cells and H1299 cells. (FIG. 2A) Vero cells wereseeded at 5×10⁵ cells per 60 mm dish and (FIG. 2B) H1299 cells wereseeded at 7.5×10⁵ cells per 60 mm dish. At 48 h post-seeding, triplicatedishes of Vero cells and H1299 cells were infected with QREO5 and KTR27at an MOI of 1 PFU/cell and 0.25 PFU/cell, respectively, in a volume of0.5 ml. The number of PFU used herein was based on their titersdetermined on U2OS cells monolayers in the presence of tetracycline.After 1.5 h of incubation at 37° C., the inocula were removed and thecells were washed twice with acid-glycine saline (to removemembrane-bound extracellular virions) and then twice by DMEM. Infectionswere carried out in the absence or presence of tetracycline at 2.5ug/ml. Infected cells were harvested at 72 h post-infection. Viraltiters were determined on U2OS monolayers in the presence oftetracycline. Viral titers are expressed as means±standard deviation.Numbers located above the brackets indicate the fold difference in viralyield between the indicated infections.

FIG. 3 shows Vero cells were seeded at 7.5×10⁵ cells per 60 mm dish.Cells were infected with QREO5 or QREO5-F at 200 PFU/dish at 48 hpost-cell seeding in the presence of tetracycline. QREO5 or QREO5-Fplaques were photographed at 48 and 72 h post-infection.

FIGS. 4A and 4B show QREO5-F and QREO5 replicate equally well in Verocells and H1299 cells. Vero cells and H1299 cells were seeded at 7.5×10⁵cells per 60 mm dish. At 48 h post-cell seeding, Vero cells (FIG. 4A)and H1299 cells (FIG. 4B) were infected with QREO5 or QREO5-F at MOIs of0.5 PFU/cell and 0.25 PFU/cell, respectively, in the presence or absenceof tetracycline. Infected cells were harvested at 72 h post-infection(FIG. 4A) or 48 h post-infection (FIG. 4B). Viral titers were determinedon U2OS monolayers in the presence of tetracycline. Viral titers areexpressed as means±standard deviation.

FIG. 5 shows no detectable VP5 expression in QREO5-F infected Vero cellsin the absence of tetrcycline. Vero cells were infected with QREO5-F atan MOI of 3 PFU/cell of in the presence and absence of tetracycline.Infected cell extracts were prepared at 16 hours post-infection,resolved by SDS-PAGE followed by western blot analysis with anti-ICP27,anti-gD, and anti-VP5 specific monoclonal antibodies.

FIG. 6 shows QREO5-F replication is tightly regulated by doxycycline.H1299 cells were seeded at 7.5×10⁵ cells per 60 mm dish. At 48 hpost-seeding, triplicate dishes of cells were infected with QREO5-F atan MOI of 0.25 PFU/cell in a volume of 0.5 ml. After 1.5 h of incubationat 37° C., the inocula were removed and the cells were washed twice withacid-glycine saline (to remove membrane-bound extracellular virions) andthen twice by DMEM. QREO5-F infections were carried out in the absenceor presence of various amounts of doxycycline. Infected cells wereharvested at 48 h post-infection. Viral titers were determined on U2OSmonolayers in the presence of tetracycline. Viral titers are expressedas means±standard deviation. Numbers located above each bar columnrepresent the fold difference in viral yield between the presence ofindicated doxycycline concentration and the absence of doxycycline.

FIGS. 7A and 7B show QREO5-F replication is efficient and highlyregulated in various human tumor cell lines. (FIG. 7A) Human cancercells MDA-MB 231, Panc-1, SK-Mel-28, SNU-398, and SK-OV-3 were seeded at1.5×10⁶, 5×10⁵, 7.5×10⁵, 1.5×10⁶ and 1.5×10⁶ cells per 60 mm dish,respectively. At 48 h post-seeding, triplicate dishes were infected withQREO5-F at MOIs of 1 PFU/cell, 0.25 PFU/cell, 3 PFU/cell, 1 PFU/cell,and 0.5 PFU/cell, respectively. After 1.5 h of incubation at 37° C., theinocula were removed and the cells were washed twice with acid-glycinesaline and then twice by DMEM. Infections were then carried out in theabsence or presence of tetracycline at 2.5 μg/ml. Infected cells wereharvested at 48, 72, 48, 48, and 72 h post-infection, respectively, andviral titers were determined on U2OS monolayers in the presence oftetracycline. (FIG. 7B) H1299, A549, and H1975 cells were seeded at7.5×10⁵, 1×10 ⁶ and 7.5×10⁵ cells per 60 mm dish, respectively. At 48 hpost-seeding, triplicate dishes were infected with QREO5-F at MOIs of0.25 PFU/cell, 0.1 PFU/cell, and 0.25 PFU/cell, respectively. After 1.5h of incubation at 37° C., the inocula were removed and the cells werewashed twice with acid-glycine saline and then twice by DMEM. Infectionswere then carried out in the absence or presence of tetracycline at 2.5μg/ml. Infected cells were harvested at 48, 72 and 48 h post-infection,respectively, and viral titers were determined on U2OS monolayers in thepresence of tetracycline. Numbers located above the brackets indicatethe fold difference in viral yield between the indicated conditions.

FIGS. 8A-8C show cytotoxicity and replication of QREO5-F aresignificantly enhanced in human lung cancer cells versus in normalprimary human fibroblasts. For results labeled “HF-serum free,” primaryhuman fibroblasts (HF) were seeded at 1.5×10⁶ cells per 60 mm dish innormal growth medium. 24 h post-seeding, normal medium was removed andreplaced with serum-free DMEM containing antibiotics. These cells wereinfected at 45 h post-serum starvation. H1299 cells were seeded at7.5×10⁵ cells per 60 mm dish in normal growth medium and infected atabout 69 h post-seeding. All cells described above were either mockinfected or infected with QREO5-F at an MOI of 0.25 PFU/cell in theabsence or presence of tetracycline at 2.5 μg/ml in DMEM containing 2%FBS. (FIG. 8A) Triplicate dishes of infected cells were harvested at 48h post-infection and viral titers were determined on U2OS monolayers inthe presence of tetracycline. (FIG. 8B) Mock-infected and infected cellsin the presence of tetracycline in triplicate dishes were harvested at72 h post-infection. Viable cells were counted by trypan blue exclusionand graphed as a percentage of viable cells in the mock-infectedcontrols, expressed as means±standard deviation. (FIG. 8C) Selectivelysis of H1299 cells. Images cells infected with QREO5-F in the absenceand presence of tetracycline, photographed at 72 h post-infection.

FIGS. 9A and 9B show therapeutic treatment of established bilateralCT26.WT tumors in normal BALB/c mice. Female BALB/c mice, 6 to7-weeks-old, were implanted s.c. with 5×10⁵ syngeneic CT26.WT coloncancer cells in a volume of 100 μl at both the left and right flanks.When subcutaneous tumors reached a diameter of tumor size of 3-5 mm,mice were divided into 3 groups of 8 mice each, in which the average oftumor size in each group is essentially the same. Mice were thenanesthetized and inoculated with DMEM containing 1 ug doxycycline,QREO5-F at 2×10⁶ PFU with or without doxycycline in a volume of 100 ulunilaterally. The number of PFU used herein was based on their titersdetermined on the ICP0-expressing Vero cell monolayers in the presenceof tetracycline. The same treatment was repeated on days 3 and 6.Volumes of injected (FIG. 9A) and contralateral (FIG. 9B) tumors werequantified every third day by a caliper using the formula V=(L×W²)/2until 21 days after treatment. Mean tumor volumes±SEM are shown.

FIGS. 10A and 10B show induction of tumor-specific memory response inQREO5-F cured mice. (FIG. 10A) Four QREO5-F cured mice and 5 naïveage-match female BALB/c mice were injected s.c. with 5×10⁵ CT26.WT cellsinto the middle section between the rear left and right flanks. Tumorvolumes were quantified every third day by a caliper. (FIG. 10B)Representative images of naïve mouse and QREO5-F-cured mouse.

DESCRIPTION OF THE INVENTION

Oncolytic viruses are genetically modified viruses that preferentiallyreplicate in host cancer cells, leading to the production of new virusesand ultimately, cell death. Herpes simplex virus (HSV) possesses severalunique properties as an oncolytic agent. It can infect a broad range ofcell types and has a short replication cycle (9 to 18 h). The use of areplication-conditional strain of HSV-1 as an oncolytic agent was firstreported for the treatment of malignant gliomas. Since then, variousefforts have been made in an attempt to broaden their therapeuticefficacy and increase the replication specificity of the virus in tumorcells. Not surprisingly, however, deletion of genes that impair viralreplication in normal cells also leads to a marked decrease in theoncolytic activity of the virus for the targeted tumor cells. Currently,no oncolytic viruses that are able to kill only tumor cells whileleaving normal cells intact are available. Consequently, the therapeuticdoses of existing oncolytic viruses are significantly restricted. Theavailability of an oncolytic virus whose replication can be tightlycontrolled and adjusted pharmacologically would offer greatly increasedsafety and therapeutic efficacy. Such a regulatable oncolytic viruswould minimize the risk of uncontrolled replication in adjacent anddistant tissues as well as undesirable progeny virus overload in thetarget area after the tumor has been eliminated. This regulatory featurewould also allow the oncolytic activity of the virus to be quickly shutdown should adverse effects be detected.

HSV replicates in epithelial cells and fibroblasts and establisheslife-long latent infection in neuronal cell bodies within the sensoryganglia of infected individuals. During productive infection, HSV genesfall into three major classes based on the temporal order of theirexpression: immediate-early (IE), early (E), and late (L) (Roizman,2001). The HSV-1 viral proteins directly relevant to the currentinvention are immediate-early regulatory protein, ICP0, and the viralmajor capsid protein ICP5 or VP5. Although not essential for productiveinfection, ICP0 is required for efficient viral gene expression andreplication at low multiplicities of infection in normal cells andefficient reactivation from latent infection (Cai and Schaffer, 1989;Leib et al., 1989; Yao and Schaffer, 1995). ICP0 is needed to stimulatetranslation of viral mRNA in quiescent cells (Walsh and Mohr, 2004) andplays a fundamental role in counteracting host innate antiviral responseto HSV infection. In brief, it prevents an IFN-induced nuclear block toviral transcription, down regulates TLR2/TLR9-induced inflammatorycytokine response to viral infection, suppresses TNF-α mediatedactivation of NF-κB signaling pathway, and interferes with DNA damageresponse to viral infection (Lanfranca et al., 2014). Given that tumorcells are impaired in various cellular pathways, such as DNA repair,interferon signaling, and translation regulation (Barber, 2015;Critchley-Thorne et al., 2009; Kastan and Bartek, 2004; Li and Chen,2018; Mohr, 2005; Zitvogel et al., 2015), it is not surprising that ICP0deletion mutants replicate much more efficiently in cancer cells than innormal cells, in particular, quiescent cells and terminallydifferentiated cells. The oncolytic potential of ICP0 mutants was firstillustrated by Yao and Schaffer (Yao and Schaffer, 1995), who showedthat the plaque-forming efficiency of an ICP0 null mutant in humanosteoscarcoma cells (U2OS) is 100- to 200-fold higher than innon-tumorigenic African green monkey kidney cells (Vero). It has beenrecently shown the defect in stimulator of interferon genes (STING)signaling pathway in U2OS cells leads to its demonstrated ability toefficiently support the growth of ICP0 null mutant (Deschamps andKalamvoki, 2017).

Using the T-RExTM gene switch technology (Thermo Fisher/Invitrogen,Carlsbad, Calif.) invented by Dr. Feng Yao and a self-cleaving ribozyme,the first regulatable oncolytic virus, KTR27 (U.S. Pat. No. 8,236,941,which is incorporated herein by reference in its entirety), in which theHSV-1 ICP0 gene is replaced by DNA sequence encoding tetracyclinerepressor (tetR) was created, while the essential HSV-1 ICP27 gene iscontrolled by the tetO-bearing ICP27 promoter and a self-cleavingribozyme in the 5′ untranslated region of the ICP27 coding sequence.Recent DNA sequence analyses of a KTR27-derived fusogenic virus, namedKTR27-F, indicates that in addition to the deletion of both copies ofICP0 gene, both copies of HSV-1 ICP34.5 gene are also deleted from thesaid KTR27-F virus. Moreover, PCR analyses of KTR27 viral DNA with theICP34.5 gene-specific primers has revealed that like KTR27-F, KTR27 doesnot encode ICP0 gene and ICP34.5 gene. ICP34.5 gene is located 5′ to theICP0 gene in the inverted repeat region of HSV-1 genome that flanks theunique long sequence of HSV-1 genome. Various HSV-1 onclytic viruses arebased on the deletion of ICP34.5 gene (Aghi and Martuza, 2005; Kaur etal., 2012; Lawler et al., 2017), including the recently FDA-approvedtalimogene laherparepvec (T-VEC) for treatment of advanced-stagemelanoma (Rehman et al., 2016).

Building on the tet-dependent viral replication and onco-selectivityprofiles of KTR27 and the notion that the self-cleaving ribozymeemployed in construction of KTR27 for achieving higher degree oftet-dependent viral replication significantly restricts viralreplication in cancer cells because of less than optimal expression ofICP27, a new ICP0 null mutant-based tetR-expressing oncolytic virusQREO5 that encodes the late HSV-1 major capsid protein VP5 under thecontrol of the tetO-containing VP5 promoter was recently developed.Because VP5 is a late viral gene product, whose expression is dependenton the expression of viral IE genes, it was hypothesized that the latekinetics of the tetO-bearing VP5 promoter would allow for more stringentcontrol of VP5 expression than that of ICP27 under the control of thetetO-bearing ICP27 promoter by tetR expressed from the IE ICP0 promoter.Indeed, QREO5 exhibits significantly superior tet-dependent viralreplication than KTR27 in infected H1299 cells and Vero cells. Moreover,because the QREO5 genome contains no self-cleaving ribozyme and encodeswild-type ICP34.5 gene, it replicates 100- and 450-fold more efficientlythan KTR27 in Vero cells and H1299 cells, respectively.

HSV-1 is a human neurotropic virus that is capable of infectingvirtually all vertebrate cells. Natural infections follow either alytic, replicative cycle or establish latency, usually in peripheralganglia, where the DNA is maintained indefinitely in an episomal state.HSV-1 contains a double-stranded, linear DNA genome, about 152 kilobasesin length, which has been completely sequenced by McGeoch (McGeoch etal., J. Gen. Virol. 69: 1531 (1988); McGeoch et al., Nucleic Acids Res14: 1727 (1986); McGeoch et al., J. Mol. Biol. 181: 1 (1985); Perry andMcGeoch, J. Gen. Virol. 69:2831 (1988); Szpara M L et al., J Virol.2010, 84:5303; Macdonald S J et al., J Virol. 2012, 86:6371). DNAreplication and virion assembly occurs in the nucleus of infected cells.Late in infection, concatemeric viral DNA is cleaved into genome lengthmolecules which are packaged into virions. In the CNS, herpes simplexvirus spreads transneuronally followed by intraaxonal transport to thenucleus, either retrograde or anterograde, where replication occurs.

Accordingly, described herein is an oncolytic Herpes Simplex Virus (HSV)comprising recombinant DNA, wherein the recombinant DNA comprises: agene comprising a 5′ untranslated region and a HSV-1, or HSV-2, VP5 genethat is operably linked to an VP5 promoter comprising a TATA element; atetracycline operator sequence positioned between 6 and 24 nucleotides3′ to said TATA element, wherein the VP5 gene lies 3′ to saidtetracycline operator sequence; a gene sequence encoding tetracyclinerepressor operably linked to an HSV immediate-early promoter, whereinthe gene sequence is located at the ICP0 locus; a variant gene thatincreases syncytium formation as compared to wild type, wherein theHSV-1, or HSV-2, variant gene is selected from the group consisting of:a glycoprotein K (gK) variant; a glycoprotein B (gB) variant; a UL24variant; and UL20 gene variant; and a gene sequence encoding afunctional ICP34.5 protein, wherein said oncolytic HSV does not encodefunctional ICP0 and does not contain a ribozyme sequence located in said5′ untranslated region of VP5. In one embodiment, the recombinant DNA isderived from the HSV-1 genome. In an alternative embodiment, therecombinant DNA is derived from the HSV-2 genome. In one embodiment, thegenome of the HSV comprising recombinant DNA consists of, consistsessentially of, or comprises the sequence of SEQ ID NO. 1.

A distinguishing feature of the oncolytic virus described herein is thatthe viral genome expression a gene sequence that encodes functionalICP34.5. Infected cell protein 34.5 (ICP34.5) is a protein (e.g., a geneproduct) expressed by the γ34.5 gene in viruses, such as the herpessimplex virus. ICP34.5 is one of HSV neurovirulence factors (Chou J,Kern E R, Whitley R J, and Roizman B, Science, 1990). One of thefunctions of ICP34.5 is to block the cellar stress response to a viralinfection, i.e., blocking the double-stranded RNA-dependent proteinkinase PKR-mediated antiviral response (Agarwalla, P. K., et al. Methodin Mol. Bio., 2012).

The oncolytic virus described herein is a ICP0 null virus. Infected cellpolypeptide 0 (ICP0) is a protein encoded by the HSV-1 α0 gene. ICP0 isgenerated during the immediate-early phase of viral gene expression.ICP0 is synthesized and transported to the nucleus of the infected hostcell, where it promotes transcription from viral genes, disrupts nuclearand cytoplasmic cellular structures, such as the microtubule network,and alters the expression of host genes. One skilled in the art candetermine if the ICP0 gene product has been deleted or if the virus doesnot express functional forms of this gene product using PCR-based assaysto detect the presence of the gene in the viral genome or the expressionof the gene products, or using functional assays to assess theirfunction, respectively.

In one embodiment, the gene that encodes these gene products contain amutation, for example, an inactivating mutation, that inhibits properexpression of the gene product. For example, the gene may encode amutation in the gene product that inhibits proper folding, expression,function, ect. of the gene product. As used herein, the term“inactivating mutation” is intended to broadly mean a mutation oralteration to a gene wherein the expression of that gene issignificantly decreased, or wherein the gene product is renderednonfunctional, or its ability to function is significantly decreased.The term “gene” encompasses both the regions coding the gene product aswell as regulatory regions for that gene, such as a promoter orenhancer, unless otherwise indicated.

Ways to achieve such alterations include: (a) any method to disrupt theexpression of the product of the gene or (b) any method to render theexpressed gene nonfunctional. Numerous methods to disrupt the expressionof a gene are known, including the alterations of the coding region ofthe gene, or its promoter sequence, by insertions, deletions and/or basechanges. (See, Roizman, B. and Jenkins, F. J., Science 229: 1208-1214(1985)).

An essential feature of the DNA of the present invention is the presenceof a gene needed for virus replication that is operably linked to apromoter having a TATA element. A tet operator sequence is locatedbetween 6 and 24 nucleotides 3′ to the last nucleotide in the TATAelement of the promoter and 5′ to the gene. The strength with which thetet repressor binds to the operator sequence is enhanced by using a formof operator which contains two op2 repressor binding sites (each suchsite having the nucleotide sequence: TCCCTATCAGTGATAGAGA (SEQ ID NO: 8))linked by a sequence of 2-20, preferably 1-3 or 10-13, nucleotides. Whenrepressor is bound to this operator, very little or no transcription ofthe associated gene will occur. If DNA with these characteristics ispresent in a cell that also expresses the tetracycline repressor,transcription of the gene will be blocked by the repressor binding tothe operator and replication of the virus will not occur. However, iftetracycline, for example, is introduced, it will bind to the repressor,cause it to dissociate from the operator, and virus replication willproceed.

During productive infection, HSV gene expression falls into three majorclasses based on the temporal order of expression: immediate-early (α),early (β), and late (γ), with late genes being further divided into twogroups, γ1 and γ2. The expression of immediate-early genes does notrequire de novo viral protein synthesis and is activated by thevirion-associated protein VP16 together with cellular transcriptionfactors when the viral DNA enters the nucleus. The protein products ofthe immediate-early genes are designated infected cell polypeptidesICP0, ICP4, ICP22, ICP27, and ICP47 and it is the promoters of thesegenes that are preferably used in directing the expression of tetrepressor (tetR). The expression of a gene needed for virus replicationis under the control of the tetO-containing promoters and theseessential genes may be immediate-early, early or late genes, e.g., ICP4,ICP27, ICP8, UL9, gD and VP5. In one embodiment, the tetR has thesequence of SEQ ID NO: 9.

ICP0 plays a major role in enhancing the reactivation of HSV fromlatency and confers a significant growth advantage on the virus at lowmultiplicities of infection. ICP4 is the major transcriptionalregulatory protein of HSV-1, which activates the expression of viralearly and late genes. ICP27 is essential for productive viral infectionand is required for efficient viral DNA replication and the optimalexpression of subset of viral β genes and γ1 genes as well as viral γ2genes. The function of ICP47 during HSV infection appears to be todown-regulate the expression of the major histocompatibility complex(MHC) class I on the surface of infected cells.

The recombinant DNA may also include at least one, and preferably atleast two, sequences coding for the tetracycline repressor withexpression of these sequences being under the control of an immediateearly promoter, preferably ICP0 or ICP4. The sequence for the HSV ICP0and ICP4 promoters and for the genes whose regulation they endogenouslycontrol are well known in the art (Perry, et al., J. Gen. Virol.67:2365-2380 (1986); McGeoch et al., J. Gen. Virol. 72:3057-3075 (1991);McGeoch et al., Nucl. Acid Res. 14:1727-1745 (1986)) and procedures formaking viral vectors containing these elements have been previouslydescribed (see US published application 2005-0266564).

These promoters are not only very active in promoting gene expression,they are also specifically induced by VP16, a transactivator releasedwhen HSV-1 infects a cell. Thus, transcription from ICP0 promoter isparticularly high when repressor is most needed to shut down virusreplication. Once appropriate DNA constructs have been produced, theymay be incorporated into HSV-1 virus using methods that are well knownin the art. One appropriate procedure is described in US 2005-0266564but other methods known in the art may also be employed.

In various embodiments, the variant gene comprises at least one aminoacid change that deviates from the wild-type sequence of the gene. Inone embodiment, an oncolytic HSV described herein can contain two ormore amino acid substitutions in at least one variant gene. The at leasttwo amino acid substitutions can be found in the same gene, for example,the gK variant gene contains at least two amino acid substitutions.Alternatively, the at least two amino acid substitutions can be found inthe at least two different genes, for example, the gK variant gene andthe UL24 variant gene each contains at least one amino acidsubstitutions.

SEQ ID NO: 2 is the amino acid sequence encoding gK (strain KOS).

(SEQ ID NO: 2) MLAVRSLQHLSTVVLITAYGLVLVWYTVFGASPLHRCIYAVRPTGTNNDTALVWMKMNQTLLFLGAPTHPPNGGWRNHAHICYANLIAGRVVPFQVPPDATNRRIMNVHEAVNCLETLWYTRVRLVVVGWFLYLAFVALHQRRCMFGVVSPAHKMVAPATYLLNYAGRIVSSVFLQYPYTKITRLLCELSVQRQNLVQLFETDPVTFLYHRPAIGVIVGCELMLRFVAVGLIVGTAFISRGACAITYPLFLTITTWCFVSTIGLTELYCILRRGPAPKNADKAAAPGRSKGLSGVCGRCCSIILSGIAMRLCYIAVVAGVVLVALHYEQEIQRRLFDV

Another distinguishing feature of the oncolytic virus described hereinis that the viral genome sequence does not contain a ribozyme sequence,for example, at the 5′ untranslated region of VP5. A ribozyme is an RNAmolecule that is capable of catalyzing a biochemical reaction in asimilar manner as a protein enzyme. Ribozymes are further described in,e.g., Yen et al., Nature 431:471-476, 2004, the contents of which areincorporated herein by reference in its entirety.

In one embodiment, the oncolytic HSV described herein further comprisesat least one polypeptide that encodes a product (e.g., a protein, agene, a gene product, or an antibody or antibody reagent) that canincrease the efficacy of the oncolytic HSV to induce ananti-tumor-specific immunity. Exemplary products include, but are notlimited to, interleukin 2 (IL2), interleukin 12 (IL12), interleukin 15(IL15), an anti-PD-1 antibody or antibody reagent, an anti-PD-L1antibody or antibody reagent, an anti-OX40 antibody or antibody reagent,a CTLA-4 antibody or antibody reagent, a TIM-3 antibody or antibodyreagent, a TIGIT antibody or antibody reagent, a soluble interleukin 10receptor (IL10R), a fusion polypeptide between a soluble IL10R andIgG-Fc domain, a soluble TGF-β type II receptor (TGFBRII), a fusionpolypeptide between a soluble TGFBRII and IgG-Fc domain, an anti-IL10Rantibody or antibody reagent, an anti-IL10 antibody or antibody reagent,an anti-TGF-β1 antibody or antibody reagent, and an anti-TGFBRIIantibody or antibody reagent. In one embodiment, the product is afragment of IL-2, IL-12, or IL-15, that comprises the same functionalityof IL-2, IL-12, or IL-15, as described herein below. One skilled in theart can determine if an anti-tumor specific immunity is induced usingstand techniques in the art, which are further described in, forexample, Clay, T M, et al. Clinical Cancer Research (2001); Malyguine,A, et al. J Transl Med (2004); or Macchia I, et al. BioMed ResearchInternational (2013), each of which are incorporated herein by referencein their entireties.

Interleukin-2 (IL-2) is an interleukin, a type of cytokine signalingmolecule in the immune system. IL-2 regulates the activities of whiteblood cells (for example, leukocytes and lymphocytes) that areresponsible for immunity. IL-2 is part of the body's natural response tomicrobial infection, and in discriminating between foreign “non-self”and “self”. It mediates its effects by binding to IL-2 receptors, whichare expressed by lymphocytes. Sequences for IL-2, also known TCGF andlympokine, are known for a number of species, e.g., human IL-2 (NCBIGene ID: 3558) polypeptide (e.g., NCBI Ref Seq NP_000577.2) and mRNA(e.g., NCBI Ref Seq NM_000586.3). IL-2 can refer to human IL-2,including naturally occurring variants, molecules, and alleles thereof.IL-2 refers to the mammalian IL-2 of, e.g., mouse, rat, rabbit, dog,cat, cow, horse, pig, and the like. The nucleic sequence of SEQ ID NO: 5comprises the nucleic sequence which encodes IL-2.

SEQ ID NO: 5 is the nucleotide sequence encoding IL-2.

(SEQ ID NO: 5)                                                            atgta 61caggatgcaa ctcctgtctt gcattgcact aagtcttgca cttgtcacaa acagtgcacc 121tacttcaagt tctacaaaga aaacacagct acaactggag catttactgc tggatttaca 181gatgattttg aatggaatta ataattacaa gaatcccaaa ctcaccagga tgctcacatt 241taagttttac atgcccaaga aggccacaga actgaaacat cttcagtgtc tagaagaaga 301actcaaacct ctggaggaag tgctaaattt agctcaaagc aaaaactttc acttaagacc 361cagggactta atcagcaata tcaacgtaat agttctggaa ctaaagggat ctgaaacaac 421attcatgtgt gaatatgctg atgagacagc aaccattgta gaatttctga acagatggat 481taccttttgt caaagcatca tctcaacact gacttgataa

Interleukin-12 (IL-12) is an interleukin naturally produced by dendriticcells, macrophages, neutrophils, and human B-lymphoblastoid cells(NC-37) in response to antigenic stimulation. IL-12 is involved in thedifferentiation of naive T cells into Th1 cells. It is known as a Tcell-stimulating factor, which can stimulate the growth and function ofT cells. It stimulates the production of interferon-gamma (IFN-γ) andtumor necrosis factor-alpha (TNF-α) from T cells and natural killer (NK)cells, and reduces IL-4 mediated suppression of IFN-γ. Sequences forIL-12a, also known P35, CLMF, NFSK, and KSF1, are known for a number ofspecies, e.g., human IL-12a (NCBI Gene ID: 3592) polypeptide (e.g., NCBIRef Seq NP_000873.2) and mRNA (e.g., NCBI Ref Seq NM 000882.3). IL-12can refer to human IL-12, including naturally occurring variants,molecules, and alleles thereof. IL-12 refers to the mammalian IL-12 of,e.g., mouse, rat, rabbit, dog, cat, cow, horse, pig, and the like. Thenucleic sequence of SEQ ID NO:6 comprises the nucleic sequence whichencodes IL-12a.

SEQ ID NO: 6 is the nucleotide sequence encoding IL-12a.

(SEQ ID NO: 6)                                            aatgtggccc cctgggtcag 241cctcccagcc accgccctca cctgccgcgg ccacaggtct gcatccagcg gctcgccctg 301tgtccctgca gtgccggctc agcatgtgtc cagcgcgcag cctcctcctt gtggctaccc 361tggtcctcct ggaccacctc agtttggcca gaaacctccc cgtggccact ccagacccag 421gaatgttccc atgccttcac cactcccaaa acctgctgag ggccgtcagc aacatgctcc 481agaaggccag acaaactcta gaattttacc cttgcacttc tgaagagatt gatcatgaag 541atatcacaaa agataaaacc agcacagtgg aggcctgttt accattggaa ttaaccaaga 601atgagagttg cctaaattcc agagagacct ctttcataac taatgggagt tgcctggcct 661ccagaaagac ctcttttatg atggccctgt gccttagtag tatttatgaa gacttgaaga 721tgtaccaggt ggagttcaag accatgaatg caaagcttct gatggatcct aagaggcaga 781tctttctaga tcaaaacatg ctggcagtta ttgatgagct gatgcaggcc ctgaatttca 841acagtgagac tgtgccacaa aaatcctccc ttgaagaacc ggatttttat aaaactaaaa 901tcaagctctg catacttctt catgctttca gaattcgggc agtgactatt gatagagtga 961tgagctatct gaatgcttcc taa

Interleukin-15 (IL-15) is an interleukin secreted by mononuclearphagocytes (and some other cells) following infection by virus(es). Thiscytokine induces cell proliferation of natural killer cells; cells ofthe innate immune system whose principal role is to kill virallyinfected cells. Sequences for IL-15 are known for a number of species,e.g., human IL-15 (NCBI Gene ID: 3600) polypeptide (e.g., NCBI Ref SeqNP_000585.4) and mRNA (e.g., NCBI Ref Seq NM_000576.1). IL-15 can referto human IL-15, including naturally occurring variants, molecules, andalleles thereof. IL-15 refers to the mammalian IL-15 of, e.g., mouse,rat, rabbit, dog, cat, cow, horse, pig, and the like. The nucleicsequence of SEQ ID NO: 7 comprises the nucleic sequence which encodesIL-15.

SEQ ID NO: 7 is the nucleotide sequence encoding IL-15.

(SEQ ID NO: 7)               atgaga atttcgaaac cacatttgag aagtatttcc atccagtgct 421acttgtgttt acttctaaac agtcattttc taactgaagc tggcattcat gtcttcattt 481tgggctgttt cagtgcaggg cttcctaaaa cagaagccaa ctgggtgaat gtaataagtg 541atttgaaaaa aattgaagat cttattcaat ctatgcatat tgatgctact ttatatacgg 601aaagtgatgt tcaccccagt tgcaaagtaa cagcaatgaa gtgctttctc ttggagttac 661aagttatttc acttgagtcc ggagatgcaa gtattcatga tacagtagaa aatctgatca 721tcctagcaaa caacagtttg tcttctaatg ggaatgtaac agaatctgga tgcaaagaat 781gtgaggaact ggaggaaaaa aatattaaag aatttttgca gagttttgta catattgtcc 841aaatgttcat caacacttct tga

Interleukin 10 receptor (IL10R), either soluble or wild-type, has beenshown to mediate the immunosuppressive signal of interleukin 10,resulting in the inhibition of the synthesis of proinflammatorycytokines. This receptor is reported to promote survival of progenitormyeloid cells through the insulin receptor substrate-2/PI 3-kinase/AKTpathway. Activation of IL10R leads to tyrosine phosphorylation of JAK1and TYK2 kinases. Two transcript variants, one protein-coding and theother not protein-coding, have been found for this gene. Sequences forIL10R are known for a number of species, e.g., human IL10R (NCBI GeneID: 3587) polypeptide (e.g., NCBI Ref Seq NP_001549.2) and mRNA (e.g.,NCBI Ref Seq NM_001558.3). IL10R can refer to human IL10R, includingnaturally occurring variants, molecules, and alleles thereof. IL10Rrefers to the mammalian IL10R of, e.g., mouse, rat, rabbit, dog, cat,cow, horse, pig, and the like. The nucleic sequence of SEQ ID NO: 3comprises the nucleic sequence which encodes IL10R.

SEQ ID NO: 3 is the nucleotide sequence encoding IL10R.

(SEQ ID NO: 3)                  atg ctgccgtgcc tcgtagtgct gctggcggcg ctcctcagcc 121tccgtcttgg ctcagacgct catgggacag agctgcccag ccctccgtct gtgtggtttg 181aagcagaatt tttccaccac atcctccact ggacacccat cccaaatcag tctgaaagta 241cctgctatga agtggcgctc ctgaggtatg gaatagagtc ctggaactcc atctccaact 301gtagccagac cctgtcctat gaccttaccg cagtgacctt ggacctgtac cacagcaatg 361gctaccgggc cagagtgcgg gctgtggacg gcagccggca ctccaactgg accgtcacca 421acacccgctt ctctgtggat gaagtgactc tgacagttgg cagtgtgaac ctagagatcc 481acaatggctt catcctcggg aagattcagc tacccaggcc caagatggcc cccgcaaatg 541acacatatga aagcatcttc agtcacttcc gagagtatga gattgccatt cgcaaggtgc 601cgggaaactt cacgttcaca cacaagaaag taaaacatga aaacttcagc ctcctaacct 661ctggagaagt gggagagttc tgtgtccagg tgaaaccatc tgtcgcttcc cgaagtaaca 721aggggatgtg gtctaaagag gagtgcatct ccctcaccag gcagtatttc accgtgacca 781acgtcatcat cttctttgcc tttgtcctgc tgctctccgg agccctcgcc tactgcctgg 841ccctccagct gtatgtgcgg cgccgaaaga agctacccag tgtcctgctc ttcaagaagc 901ccagcccctt catcttcatc agccagcgtc cctccccaga gacccaagac accatccacc 961cgcttgatga ggaggccttt ttgaaggtgt ccccagagct gaagaacttg gacctgcacg 1021gcagcacaga cagtggcttt ggcagcacca agccatccct gcagactgaa gagccccagt 1081tcctcctccc tgaccctcac ccccaggctg acagaacgct gggaaacagg gagccccctg 1141tgctggggga cagctgcagt agtggcagca gcaatagcac agacagcggg atctgcctgc 1201aggagcccag cctgagcccc agcacagggc ccacctggga gcaacaggtg gggagcaaca 1261gcaggggcca ggatgacagt ggcattgact tagttcaaaa ctctgagggc cgggctgggg 1321acacacaggg tggctcggcc ttgggccacc acagtccccc ggagcctgag gtgcctgggg 1381aagaagaccc agctgctgtg gcattccagg gttacctgag gcagaccaga tgtgctgaag 1441agaaggcaac caagacaggc tgcctggagg aagaatcgcc cttgacagat ggccttggcc 1501ccaaattcgg gagatgcctg gttgatgagg caggcttgca tccaccagcc ctggccaagg 1561gctatttgaa acaggatcct ctagaaatga ctctggcttc ctcaggggcc ccaacgggac 1621agtggaacca gcccactgag gaatggtcac tcctggcctt gagcagctgc agtgacctgg 1681gaatatctga ctggagcttt gcccatgacc ttgcccctct aggctgtgtg gcagccccag 1741gtggtctcct gggcagcttt aactcagacc tggtcaccct gcccctcatc tctagcctgc 1801agtcaagtga gtga

Transforming growth factor beta receptor II (TGFBRII), either soluble orwild type form, is protein encoded by this gene forms a heteromericcomplex with type II TGF-beta receptors when bound to TGF-beta,transducing the TGF-beta signal from the cell surface to the cytoplasm.Sequences for TGFBRII are known for a number of species, e.g., humanTGFBRII (NCBI Gene ID: 7048) polypeptide (e.g., NCBI Ref SeqNP_001020018.1) and mRNA (e.g., NCBI Ref Seq NM_001024847.2). TGFBRIIcan refer to human TGFBRII, including naturally occurring variants,molecules, and alleles thereof. TGFBRII refers to the mammalian TGFBRIIof, e.g., mouse, rat, rabbit, dog, cat, cow, horse, pig, and the like.The nucleic sequence of SEQ ID NO: 4 comprises the nucleic sequencewhich encodes TGFBRII.

SEQ ID NO: 4 is the nucleotide sequence encoding TGFBRII.

(SEQ ID NO: 4)                        ATGGGTCG GGGGCTGCTC AGGGGCCTGT GGCCGCTGCA 421CATCGTCCTG TGGACGCGTA TCGCCAGCAC GATCCCACCG CACGTTCAGA AGTCGGATGT 481GGAAATGGAG GCCCAGAAAG ATGAAATCAT CTGCCCCAGC TGTAATAGGA CTGCCCATCC 541ACTGAGACAT ATTAATAACG ACATGATAGT CACTGACAAC AACGGTGCAG TCAAGTTTCC 601ACAACTGTGT AAATTTTGTG ATGTGAGATT TTCCACCTGT GACAACCAGA AATCCTGCAT 661GAGCAACTGC AGCATCACCT CCATCTGTGA GAAGCCACAG GAAGTCTGTG TGGCTGTATG 721GAGAAAGAAT GACGAGAACA TAACACTAGA GACAGTTTGC CATGACCCCA AGCTCCCCTA 781CCATGACTTT ATTCTGGAAG ATGCTGCTTC TCCAAAGTGC ATTATGAAGG AAAAAAAAAA 841GCCTGGTGAG ACTTTCTTCA TGTGTTCCTG TAGCTCTGAT GAGTGCAATG ACAACATCAT 901CTTCTCAGAA GAATATAACA CCAGCAATCC TGACTTGTTG CTAGTCATAT TTCAAGTGAC 961AGGCATCAGC CTCCTGCCAC CACTGGGAGT TGCCATATCT GTCATCATCA TCTTCTACTG 1021CTACCGCGTT AACCGGCAGC AGAAGCTGAG TTCAACCTGG GAAACCGGCA AGACGCGGAA 1081GCTCATGGAG TTCAGCGAGC ACTGTGCCAT CATCCTGGAA GATGACCGCT CTGACATCAG 1141CTCCACGTGT GCCAACAACA TCAACCACAA CACAGAGCTG CTGCCCATTG AGCTGGACAC 1201CCTGGTGGGG AAAGGTCGCT TTGCTGAGGT CTATAAGGCC AAGCTGAAGC AGAACACTTC 1261AGAGCAGTTT GAGACAGTGG CAGTCAAGAT CTTTCCCTAT GAGGAGTATG CCTCTTGGAA 1321GACAGAGAAG GACATCTTCT CAGACATCAA TCTGAAGCAT GAGAACATAC TCCAGTTCCT 1381GACGGCTGAG GAGCGGAAGA CGGAGTTGGG GAAACAATAC TGGCTGATCA CCGCCTTCCA 1441CGCCAAGGGC AACCTACAGG AGTACCTGAC GCGGCATGTC ATCAGCTGGG AGGACCTGCG 1501CAAGCTGGGC AGCTCCCTCG CCCGGGGGAT TGCTCACCTC CACAGTGATC ACACTCCATG 1561TGGGAGGCCC AAGATGCCCA TCGTGCACAG GGACCTCAAG AGCTCCAATA TCCTCGTGAA 1621GAACGACCTA ACCTGCTGCC TGTGTGACTT TGGGCTTTCC CTGCGTCTGG ACCCTACTCT 1681GTCTGTGGAT GACCTGGCTA ACAGTGGGCA GGTGGGAACT GCAAGATACA TGGCTCCAGA 1741AGTCCTAGAA TCCAGGATGA ATTTGGAGAA TGTTGAGTCC TTCAAGCAGA CCGATGTCTA 1801CTCCATGGCT CTGGTGCTCT GGGAAATGAC ATCTCGCTGT AATGCAGTGG GAGAAGTAAA 1861AGATTATGAG CCTCCATTTG GTTCCAAGGT GCGGGAGCAC CCCTGTGTCG AAAGCATGAA 1921GGACAACGTG TTGAGAGATC GAGGGCGACC AGAAATTCCC AGCTTCTGGC TCAACCACCA 1981GGGCATCCAG ATGGTGTGTG AGACGTTGAC TGAGTGCTGG GACCACGACC CAGAGGCCCG 2041TCTCACAGCC CAGTGTGTGG CAGAACGCTT CAGTGAGCTG GAGCATCTGG ACAGGCTCTC 2101GGGGAGGAGC TGCTCGGAGG AGAAGATTCC TGAAGACGGC TCCCTAAACA CTACCAAATA 2161GCTCTTCTGG

Antibodies or antibody reagents that bind to PD-1, or its ligand PD-L1,are described in, e.g., U.S. Pat. Nos. 7,488,802; 7,943,743; 8,008,449;8,168,757; 8,217,149, and PCT Published Patent Application Nos:WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342,WO2011159877, WO2011082400, and WO2011161699; which are incorporated byreference herein in their entireties. In certain embodiments the PD-1antibodies include nivolumab (MDX 1106, BMS 936558, ONO 4538), a fullyhuman IgG4 antibody that binds to and blocks the activation of PD-1 byits ligands PD-L1 and PD-L2; lambrolizumab (MK-3475 or SCH 900475), ahumanized monoclonal IgG4 antibody against PD-1; CT-011 a humanizedantibody that binds PD-1; AMP-224, a fusion protein of B7-DC; anantibody Fc portion; BMS-936559 (MDX-1105-01) for PD-L1 (B7-H1)blockade. Also specifically contemplated herein are agents that disruptor block the interaction between PD-1 and PD-L1, such as a high affinityPD-L1 antagonist.

Non-limiting examples of PD-1 antibodies include: pembrolizumab (Merck);nivolumab (Bristol Meyers Squibb); pidilizumab (Medivation); and AUNP12(Aurigene). Non-limiting examples of PD-L1 antibodies can includeatezolizumab (Genentech); MPDL3280A (Roche); MED14736 (AstraZeneca);MSB0010718C (EMD Serono); avelumab (Merck); and durvalumab (Medimmune).

Antibodies that bind to OX40 (also known as CD134), are described in,e.g., U.S. Pat. Nos. 9,006,399, 9,738,723, 9,975,957, 9,969,810,9,828,432; PCT Published Patent Application Nos: WO2015153513,WO2014148895, WO2017021791, WO2018002339; and US Application Nos:US20180273632; US20180237534; US20180230227; US20120269825; which areincorporated by reference herein in their entireties.

Antibodies that bind to CTLA-4, are described in, e.g., U.S. Pat. Nos.9,714,290, 6,984,720, 7,605,238, 6,682,736, 7,452,535; PCT PublishedPatent Application No: WO2009100140; and US Application Nos:US20090117132A, US20030086930, US20050226875, US20090238820; which areincorporated by reference herein in their entireties. Non-limitingexamples of CTLA-4 antibodies include: ipilimumab (Bristol-Myers Squibb)

Antibodies that bind to TIM3, are described in, e.g., U.S. Pat. Nos.8,552,156, 9,605,070, 9,163,087, 8,329,660; PCT Published PatentApplication No: WO2018036561, WO2017031242, WO2017178493; and USApplication Nos: US20170306016, US201501 10792, US20180057591,US20160200815; which are incorporated by reference herein in theirentireties.

Antibodies that bind to TIGIT (also known as CD134), are described in,e.g., U.S. Pat. Nos. 10,017,572, 9,713,641; PCT Published PatentApplication No: WO2017030823; and US Application Nos: US20160355589,US20160176963, US20150322119; which are incorporated by reference hereinin their entireties.

Antibodies that bind to Interleukin 10 receptor (IL10R) (e.g., solubleor wild-type) are described in, e.g., U.S. Pat. No. 7,553,932; and USApplication Nos: US20040009939, US20030138413, US20070166307,US20090087440, and US201000028450, which are incorporated by referenceherein in their entireties.

Antibodies that bind to TGFBRII (e.g., soluble or wild-type) aredescribed in, e.g., U.S. Pat. No. 6,497,729; and US Application Nos:US2012114640, US20120021519, which are incorporated by reference hereinin their entireties.

In one embodiment, the oncolytic HSV described herein further encodesfusogenic activity.

Another aspect provides an oncolytic Herpes Simplex Virus (HSV)comprising recombinant DNA that does not encode functional ICP0 andencodes fusogenic activity.

One aspect of the invention described herein provides a compositioncomprising any of the oncolytic HSV described herein. In one embodiment,the composition is a pharmaceutical composition. As used herein, theterm “pharmaceutical composition” refers to the active agent incombination with a pharmaceutically acceptable carrier e.g. a carriercommonly used in the pharmaceutical industry.

In one embodiment, the composition further comprises at least onepharmaceutically acceptable carrier. Pharmaceutically acceptablecarriers are well known in the art and include aqueous solutions such asphysiologically buffered saline or other solvents or vehicles such asglycols, glycerol, vegetable oils (e.g., olive oil) or injectableorganic esters. A pharmaceutically acceptable carrier can be used toadminister the compositions of the invention to a cell in vitro or to asubject in vivo. A pharmaceutically acceptable carrier can contain aphysiologically acceptable compound that acts, for example, to stabilizethe composition or to increase the absorption of the agent. Aphysiologically acceptable compound can include, for example,carbohydrates, such as glucose, sucrose or dextrans, antioxidants, suchas ascorbic acid or glutathione, chelating agents, low molecular weightproteins or other stabilizers or excipients. Other physiologicallyacceptable compounds include wetting agents, emulsifying agents,dispersing agents or preservatives, which are particularly useful forpreventing the growth or action of microorganisms. Various preservativesare well known and include, for example, phenol and ascorbic acid. Oneskilled in the art would know that the choice of a pharmaceuticallyacceptable carrier, including a physiologically acceptable compound,depends, for example, on the route of administration of the oncolyticHSV.

The oncolytic viruses described herein or composition thereof can beadministered to a subject having cancer. In one embodiment, an agentthat regulates the tet operator is further administered with theoncolytic viruses described herein or composition thereof. Exemplaryagents include, but are not limited to, doxycycline or tetracycline.

In one embodiment, the cancer is a solid tumor. The solid tumor can bemalignant or benign. In one embodiment, the subject is diagnosed or hasbeen diagnosed with having a carcinoma, a melanoma, a sarcoma, a germcell tumor, and a blastoma. Exemplary cancers include, but are in no waylimited to, non-small-cell lung cancer, breast cancer, brain cancer,colon cancer, prostate cancer, liver cancer, lung cancer, ovariancancer, skin cancer, head and neck cancer, kidney cancer, and pancreaticcancer. In one embodiment, the cancer is metastatic. These types ofcancers are known in the art and can be diagnosed by a skilled clinicianusing standard techniques known in the art, for example blood analysis,blood cell count analysis, tissue biopsy, non-invasive imaging, and/orreview of family history.

In cases where tumors are readily accessible, e.g., tumors of the skin,mouth or which are accessible as the result of surgery, virus can beapplied topically. In other cases, it can be administered by injectionor infusion. The agent that regulates the tet operator and tetRinteraction, for example doxycycline or tetracycline, used prior toinfection or at a time of infection can also be administered in this wayor it can be administered systemically, for example, orally.

Although certain routes of administration are provided in the foregoingdescription, according to the invention, any suitable route ofadministration of the vectors may be adapted, and therefore the routesof administration described above are not intended to be limiting.Routes of administration may include, but are not limited to,intravenous, regional artery infusion, oral, buccal, intranasal,inhalation, topical application to a mucosal membrane or injection,including intratumoral, intradermal, intrathecal, intracisternal,intralesional or any other type of injection. Administration can beeffected continuously or intermittently and will vary with the subjectand the condition to be treated. One of skill in the art would readilyappreciate that the various routes of administration described hereinwould allow for the inventive vectors or compositions to be deliveredon, in, or near the tumor or targeted cancer cells. One of skill in theart would also readily appreciate that various routes of administrationdescribed herein will allow for the vectors and compositions describedherein to be delivered to a region in the vicinity of the tumor orindividual cells to be treated. “In the vicinity” can include any tissueor bodily fluid in the subject that is in sufficiently close proximityto the tumor or individual cancer cells such that at least a portion ofthe vectors or compositions administered to the subject reach theirintended targets and exert their therapeutic effects.

Prior to administration, the oncolytic viruses can be suspended in anypharmaceutically acceptable solution including sterile isotonic saline,water, phosphate buffered saline, 1,2-propylene glycol, polyglycolsmixed with water, Ringer's solution, etc. The exact number of viruses tobe administered is not crucial to the invention but should be an“effective amount,” i.e., an amount sufficient to cause cell lysisextensive enough to generate an immune response to released tumorantigens. Since virus is replicated in the cells after infection, thenumber initially administered will increase rapidly with time. Thus,widely different amounts of initially administered virus can give thesame result by varying the time that they are allowed to replicate,i.e., the time during which cells are exposed to tetracycline. Ingeneral, it is expected that the number of viruses (PFU) initiallyadministered will be between 1×10⁶ and 1×10¹⁰.

Tetracycline or doxycycline will be administered either locally orsystemically to induce viral replication at a time of infection or 1-72h prior to infection. The amount of tetracycline or doxycycline to beadministered will depend upon the route of delivery. In vitro, 1 μg/mlof tetracycline is more than sufficient to allow viral replication ininfected cells. Thus, when delivered locally, a solution containinganywhere from 0.1 μg/ml to 100 μg/ml may be administered. However, muchhigher doses of tetracycline or doxycycline (e.g., 1-5 mg/ml) can beemployed if desired. The total amount given locally at a single timewill depend on the size of the tumor or tumors undergoing treatment butin general, it is expected that between 0.5 and 200 ml of tetracyclineor doxycycline solution would be used at a time. When givensystemically, higher doses of tetracycline or doxycycline will be givenbut it is expected that the total amount needed will be significantlyless than that typically used to treat bacterial infections (forexample, with doxycycline, usually 1-2 grams per day in adults dividedinto 2-4 equal doses and, in children, 2.2-4.4 mg per kilogram of bodyweight, which can be divided into at least 2 doses, per day). It isexpected that 5-100 mg per day should be effective in most cases. Dosingfor tetracycline and doxycycline are well known in the art and can bestbe determined by a skilled clinician for a given patient.

The effectiveness of a dosage, as well as the effectiveness of theoverall treatment can be assessed by monitoring tumor size usingstandard imaging techniques over a period of days, weeks and/or months.A shrinkage in the size or number of tumors is an indication that thetreatment has been successful. If this does not occur or continue, thenthe treatment can be repeated as many times as desired. In addition,treatment with virus can be combined with any other therapy typicallyused for solid tumors, including surgery, radiation therapy orchemotherapy. In addition, the procedure can be combined with methods orcompositions designed to help induce an immune response.

As used herein, the term “therapeutically effective amount” is intendedto mean the amount of vector which exerts oncolytic activity, causingattenuation or inhibition of tumor cell proliferation, leading to tumorregression. An effective amount will vary, depending upon the pathologyor condition to be treated, by the patient and his or her status, andother factors well known to those of skill in the art. Effective amountsare easily determined by those of skill in the art. In some embodimentsa therapeutic range is from 103 to 10¹² plaque forming units introducedonce. In some embodiments a therapeutic dose in the aforementionedtherapeutic range is administered at an interval from every day to everymonth via the intratumoral, intrathecal, convection-enhanced,intravenous or intra-arterial route.

The invention provided herein can further be described in the followingnumbered paragraphs.

-   1. An oncolytic Herpes Simplex Virus (HSV) comprising recombinant    DNA, wherein the recombinant DNA comprises:    -   a) a gene comprising a 5′ untranslated region and a HSV-1, or        HSV-2, VP5 gene that is operably linked to an VP5 promoter        comprising a TATA element;    -   b) a tetracycline operator sequence positioned between 6 and 24        nucleotides 3′ to said TATA element, wherein the VP5 gene lies        3′ to said tetracycline operator sequence; c) a gene sequence        encoding tetracycline repressor operably linked to an HSV        immediate-early promoter, wherein the gene sequence is located        at the ICP0 locus;    -   d) a variant gene that increases syncytium formation as compared        to wild type, wherein the HSV-1, or HSV-2, variant gene is        selected from the group consisting of: a glycoprotein K (gK)        variant; a glycoprotein B (gB) variant; a UL24 variant; and UL20        gene variant; and    -   e) a gene sequence encoding a functional ICP34.5 protein;    -   wherein said oncolytic HSV does not encode functional ICP0 and        does not contain a ribozyme sequence located in said 5′        untranslated region of VP5.    -   2. The oncolytic HSV of paragraph 1, wherein the variant gene is        a gK variant gene that encodes an amino acid substitution        selected from the group consisting of: an Ala to Thr amino acid        substitution corresponding to amino acid 40 of SEQ ID NO: 2; an        Ala to “x” amino acid substitution corresponding to amino acid        40 of SEQ ID NO: 2, wherein “x” is any amino acid; an Asp to Asn        amino acid substitution corresponding to amino acid 99 of SEQ ID        NO: 2; a Leu to Pro amino acid substitution corresponding to        amino acid 304 of SEQ ID NO: 2; and an Arg to Leu amino acid        substitution corresponding to amino acid 310 of SEQ ID NO: 2.    -   3. The oncolytic HSV of any preceding paragraph, wherein the        tetracycline operator sequence comprises two Op2 repressor        binding sites.    -   4. The oncolytic HSV of any preceding paragraph, wherein the VP5        promoter is an HSV-1 or HSV-2 VP5 promoter.    -   5. The oncolytic HSV of any preceding paragraph, wherein the        immediate-early promoter is an HSV-1 or HSV-2 immediate-early        promoter.    -   6. The oncolytic HSV of any preceding paragraph, wherein the HSV        immediate-early promoter is selected from the group consisting        of: ICP0 promoter and ICP4 promoter.    -   7. The oncolytic HSV of any preceding paragraph, wherein the        recombinant DNA is part of the HSV-1 genome.    -   8. The oncolytic HSV of any preceding paragraph, wherein the        recombinant DNA is part of the HSV-2 genome.    -   9. The oncolytic HSV of any preceding paragraph, further        comprising a pharmaceutically acceptable carrier.    -   10. The oncolytic HSV of any preceding paragraph, further        encoding at least one polypeptide that can increase the efficacy        of the oncolytic HSV to induce an anti-tumor-specific immunity.    -   11. The oncolytic HSV of any preceding paragraph, wherein the at        least one polypeptide encodes a product selected from the group        consisting of: interleukin 2 (IL2), interleukin 12 (IL12),        interleukin 15 (IL15), an anti-PD-1 antibody or antibody        reagent, an anti-PD-L1 antibody or antibody reagent, an        anti-OX40 antibody or antibody reagent, a CTLA-4 antibody or        antibody reagent, a TIM-3 antibody or antibody reagent, a TIGIT        antibody or antibody reagent, a soluble interleukin 10 receptor        (IL10R), a fusion polypeptide between a soluble IL10R and IgG-Fc        domain, a soluble TGFβ receptor (TGFBRII), a fusion polypeptide        between a soluble TGFBRII and IgG-Fc domain, an anti-IL10R        antibody or antibody reagent, an anti-IL10 antibody or antibody        reagent, an anti-TGFβ1 antibody or antibody reagent, and an        anti-TGFBRII antibody or antibody reagent.    -   12. The oncolytic HSV of any preceding paragraph, wherein the        oncolytic HSV the further encodes fusogenic activity.    -   13. A composition comprising an oncolytic HSV of any preceding        paragraph.    -   14. The composition of any preceding paragraph, further        comprising a pharmaceutically acceptable carrier.    -   15. A method for treating cancer, the method comprising        administering the oncolytic HSV of any preceding paragraph or        the composition of any preceding paragraph to a subject having        cancer.    -   16. The method of any preceding paragraph, wherein the cancer is        a solid tumor.    -   17. The method of any preceding paragraph, wherein the tumor is        benign or malignant.    -   18. The method of any preceding paragraph, wherein the subject        is diagnosed or has been diagnosed as having cancer is selected        from the list consisting of: a carcinoma, a melanoma, a sarcoma,        a germ cell tumor, and a blastoma.    -   19. The method of any preceding paragraph, wherein the subject        is diagnosed or has been diagnosed as having a cancer selected        from the group consisting of: non-small-cell lung cancer, breast        cancer, brain cancer, colon cancer, prostate cancer, liver        cancer, lung cancer, ovarian cancer, skin cancer, head and neck        cancer, kidney cancer, and pancreatic cancer.    -   20. The method of any preceding paragraph, wherein the cancer is        metastatic.    -   21. The method of any preceding paragraph, further comprising        administering an agent that regulates the tet        operator-containing promoter.    -   22. The method of any preceding paragraph, wherein the agent is        doxycycline or tetracycline.    -   23. The method of any preceding paragraph, wherein the agent is        administered locally or systemically.    -   24. The method of any preceding paragraph, wherein the systemic        administration is oral administration.    -   25. The method of any preceding paragraph, wherein the oncolytic        virus is administered directly to the tumor.    -   26. An oncolytic Herpes Simplex Virus (HSV) comprising        recombinant DNA, wherein the recombinant DNA does not encode        functional ICP0; and encodes fusogenic activity.

Examples Introduction

Human cancers are heterogeneous and contain multiple barriers that limitviruses from efficiently infecting distant tumor cells following initialviral replication (McKee et al., 2006; Nagano et al., 2008; Pluen etal., 2001). It has been elegantly demonstrated that intratumoralinoculation of oncolytic viruses enabling expression of viral fusogenicglycoproteins lead to syncytium formation of infected cells withneighboring cells, resulting in more efficient spread of viruses withinthe tumor as well as bystander killing of uninfected tumor cells throughsyncytium formation (Ahmed et al., 2003; Fu et al., 2003). It has beenfurther indicated that syncytia caused by fusogenic lysis of tumor cellsleads to the more efficient release and cross presentation of tumorantigens for priming tumor-specific T-cell response (Errington et al.,2006; Phan et al., 2003). Without being bound by a particular theory, itwas thus hypothesized that a fusogenic variant of QREO5 could offer asignificant immunological benefit in augmenting the anti-tumor responseinduced by QREO5.

HSV encodes several surface glycoproteins that involve the fusion of theviral envelope with the cell membrane as well as the fusion of aninfected cell with adjacent cells, leading to syncytia. HSV variantsexhibiting extensive syncytium formation consisting of as many asthousands of nuclei can be isolated by the propagation of virus in cellcultures (Pertel and Spear, Virology, 1996). Studies have shown thatmutations in the cytoplasmic domain of HSV-1 glycoprotein B (gB) canlead to extensive syncytial (Baghian A et al., J Virol. 67:2396-2401,1993; Bzik D J et al., Virology 137:185-190, 1984; Cai W H et al., JVirol 62:2596-2604, 1988; Engel J P et al., Virology 192:112-120, 1993;Diakidi-Kosta A et al., Gage P J et al., J Virol 67:2191-2201, 1993;Virus Res 93-99-108, 2003). HSV-1 syncytial mutations have also beenidentified in gene encoding for glycoprotein K (gK) (Bond V C et al., JGen Virol 61:245-254, 1982; Bond V C and Person S, Virology 132:368-376,1984; Debroy C et al., et al., Virology 145:36-48, 1985; Hutchinson etal., J Virol 66:5603-5609; Pogue-Geile K L et al., Virology 136:100-109,1984; Pogue-Geile K L et al., Virology 157:67-74, 1987), the UL20 gene(Melancon J M et al., J Virol 78:7329-7343, 2004) and the UL24 gene(Sanders P G et al., J Gen Virol 63:277-95, 1982; Jacobson J G et al., JVirol 63:1839-1843; Jacobson J G et al., Virology 242:161-169, 1998).Notably, UL20 interacts with both gB and gK (Foster T P et al., J Virol82:6310-6323, 2008; Chouljenko V N et al., J Virol 84:8596-8606).

QREO5-F is a syncytium-forming QREO5 variant isolated by continuingpropagations of QREO5 in human osteosarcama U2OS cells followed byplaque-purification. Due to its robust fusogenic activity, QREO5-F issignificantly more efficient than QREO5 in killing infected cancer cellsat the low multiplicity of infection. QREO5-F and QREO5 replicateequally well in Vero cells and H1299 human lung cancer cells. It isshown herein that infection of multiple human cancer cell types withQREO5-F led to 36,000-to 5×10⁷-fold tetracycline-dependent progeny virusproduction. Importantly, it is shown herein that QREO5-F is highlyeffective against pre-established CT26.WT colon carcinoma tumor inimmune-competent mice. Moreover, localized intratumoral QREO5-Fvirotherapy led to induction of effective tumor-specific immunity thatcan prevent the tumor growth following re-challenge with the same typeof tumor cells.

Materials and Methods

Cells, plasmids, and viruses. The osteosarcoma line U2OS and the Africangreen monkey kidney cell line (Vero) were grown in Dulbecco's modifiedEagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS)(Yao and Schaffer, 1995). U2OS cells express a cellular activity thatcan effectively complement the function of the HSV-1 IE regulatoryprotein ICP0 lacking in ICP0-mutant viruses (Yao and Schaffer, 1995).Primary human fibroblasts were grown in DMEM containing 10% FBS plus1×non-essential amino acids (Yao and Eriksson, 1999).

Human breast cancer cells (MDA-MB-231), human colon cancer cells(HCT116), human non-small-cell lung cancer cells (H1299, A549, H1975),human liver cancer cells (SNU-398), and pancreatic cancer cells (Panc 1)were cultured in DMEM containing 10% FBS. Human melanoma cells(SK-MEL-28) were cultured in DMEM containing 10% FBS plus 1×non-essential amino acids and 1 mM sodium pyruvate. Human ovarian cancercells (SK-OV-3) were cultured in RPMI-1640 medium containing 2 mMglutamine and 10% FBS. H1975 cells and SNU-398 cells were kindlyprovided by Dr. Chris A. French (Brigham and Women's Hospital) and Dr.Li Chai (Brigham and Women's Hospital), respectively. Panc 1 was thekind gift of Dr. Edward Hwang (Brigham and Women's Hospital). HCT116cells were kindly provided by Dr. Albert Koong (Stanford University).Mouse colorectal carcinoma cells CT26.WT were purchased from ATCC andcultured in in DMEM containing 10% FBS.

pVP5 is an HSV-1 VP5-expressing plasmid, which was constructed byinsertion of the Bgl II-Afe I-VP5 containing fragment of pKK1 intopcDNA3 at the Bgl II and Xho I sites. pKK1 was kindly provided by Dr.Prashant J. Desai (John Hopkins University). pTO-VP5 is a pVP5-derivedplasmid, in which the expression of VP5 is under the control of thetetO-containing VP5 promoter.

KOR is an HSV-1 strain KOS derived ICP0 null mutant virus that encodestetracycline repressor (tetR) at the ICP0 locus (Yao et al., 2006).K0R27-lacZ was derived from KOR in which the ICP27 coding sequence wasreplaced with the LacZ gene by homologous recombination (Yao et al.,2010). KTR27 is a 7134-derived recombinant virus that encodes tetR underthe control of HSV-1 ICP0 promoter at the ICP0 locus, and the essentialICP27 gene under the control of the tetO-containing ICP27 promoter and aself-cleaving ribozyme located at the 5′ untranslated region of ICP27coding sequence (Yao et al., 2010) (U.S. Pat. No. 8,236,941). K5AZ is aHSV-1 strain KOS-derived VP5-deletion mutant virus (Kindly provided byDr. Prashant J. Desai, John Hopkins University), in which the HSV-1 VP5gene is replaced by the LacZ gene. KTO-VP5 is a K5AZ-derived virus,which was constructed by replacing the lacZ in K5AZ with VP5 gene underthe control of the tetO-containing VP5 promoter in plasmid pTO-VP5according to protocol as previously described (Yao et al., 2010).

SDS-PAGE and western blot analysis. 60-mm dishes of Vero cells induplicate were infected QREO5-F at an MOI of 3 PFU/cell in the absenceand presence of tetracycline. Cell extracts were prepared at 16 hourspost-infection as described previously (Yao and Schaffer, 1995).Proteins in cell extracts were resolved by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred topolyvinylidene difluoride (PVDF) membranes. Western blot analyses wereperformed (Yao and Schaffer, 1995) with monoclonal antibodies (SantaCruz Biotechnology, Inc., Santa Cruz, Calif.) specific for HSV IEproteins ICP27 (sc-69806), and early-late gene products VP5 (sc-56989)and gD (sc-69802).

Mice and experimental tumors. Female BALB/c mice 6-7 weeks of age werepurchased from Charles River Laboratories (Cambridge, Mass.). Mice werehoused in metal cages at four mice per cage and maintained on a 12-hlight/dark cycle. Mice were allowed to acclimatize for one week prior toexperimentation. All animal experiments conducted in this study wereapproved by the Harvard Medical Area Standing Committee on Animals andthe American Veterinary Medical Association, which is accredited by theAssociation for Assessment and Accreditation of Laboratory Animal Care(AAALAC) and meets National Institutes of Health standards as set forthin “The Guide for the Care and Use of Laboratory Animals.”

A syngeneic mouse colon carcinoma model was established by implantations.c. of 5×10⁵ CT26. WT cells in a volume of 100 μl in both the left andright flanks of female BALB/c mice (n=24). Once tumors reached to 3-5 mmin diameter, mice were randomly divided into 3 different groups of 8mice each, and tumors on one side of flanks were intratumorally injectedwith 100 ul of DMEM containing 1 ug of doxycycline, QREO5-F at 2×10⁶ PFUcontaining no doxycycline, or QREO5-F at 2×10⁶ PFU containing 1 ugdoxycycline in a volume of 100 ul. The number of PFU used herein wasbased on the titer on the ICP0-expressing Vero cells monolayers in thepresence of tetracycline. Tumors were received the same treatment ondays 3 and 6 post initial inoculation. Tumor volumes were quantifiedevery third day using calipers and the formula V=(L×W²)/2. Data arepresented as means±SEM.

Illumina sequencing. QREO5-F viral DNA was prepared fromQREO5-F-infected U2OS cells with Qiagen Genomic DNA kit. Quantitativereal-time PCR analysis reveals close to 80% of total DNA representsQREO5-F viral DNA. The isolated DNA (2.2 ug) was used for libraryconstruction and sequencing at Translational Genomics Core Facility,Partners HealthCare, Cambridge, Mass. Briefly, DNA was sheared to anaverage size of 550 bp, which then underwent library construction perthe manufacturer's manual (Illumina TruSeq DNA PCR-Free SamplePreparation Kit). Libraries were then sequenced on the MiSeq instrument(Illumina) to generate 250 bp paired end reads. For both libraries, thesequencing yielded greater than 1,500,000 total pass filtered (PF)reads.

Genome assembly and variant calling was performed using the VirAMPpipeline on the web-based interface (Wan Y et al., 2015;www.viramp.com), using default paired-end sequence settings. VirAmp usesa semi-guided de novo assembly where assembly of short sequence readsinto contigs is followed by a reference guided assembly to orientcontigs and perform pairwise alignment. Variant calling uses MUMmerpackage tools to identify variation between the new assemblies and thereference sequence. The HSV-1 KOS strain (JQ673480.1) was used as thereference sequence for the assembly, as well as for variant calling.

Results

Construction and selection of QREO5. QREO5 is an HSV-1 recombinant virusthat encodes tetR under the control of HSV-1 ICP0 promoter at the ICP0locus, and the essential VP5 gene under the control of thetetO-containing VP5 promoter (FIG. 1 ). QREO5 was constructed first byco-infection of U2OS cells with KTO-VP5 and K0R27-lacZ followedplaque-purification on U2OS cells. The plaque-purified virus thatexhibits highly tetracycline-dependent viral replication in U2OS cellsand Vero cells was then propagated in MCF-7 human breast cancer cellsfor several passages followed by three round of plaque-purification.

Replication of QREO5 in Vero cells and H1299 cells. To test if QREO5replicates more efficiently than KTR27 in Vero cells, and if thereplication of QREO5 can be more stringently controlled by tetracycline,Vero cells were infected with QREO5 and KTR27 at an MOI of 1 PFU/cell inthe absence and presence of tetracycline and infected cells wereharvested at 72 h post-infection. As shown in FIG. 2A, yields of QREO5in Vero cells is 10⁵-fold higher than KTR27, and the fold oftetracycline-dependent viral replication of QREO5 in Vero cells issignificant higher than that of KTR27. The result in FIG. 2B shows thatyields of QREO5 is 450-fold higher than KTR27 in H1299 cells at an MOIof 0.25 PFU/cell.

Selection of QREO5-F. To isolate fusogenic variants of QREO5, fusogenicvariants-containing QREO5 stock was propagated in U2OS cells for 7 morepassages. Fifty large fusogenic variants of QREO5 were plaque-purifiedand amplified in U2OS cells followed by testing their plaque-formingefficiency in U2OS cells, H1299 cells, A549, and MCF7 cells. QREO5-F isa second-round plaque-purified syncytium-forming QREO5 variant with aplaque size ˜ 30 times larger than that of parental QREO5 at 48 and 72 hpost-infection in infected Vero cells (FIG. 3 ). QREO5-F replicates inVero cells and H1299 cells as efficiently as QREO5 (FIG. 4 ).

The western blot analyses presented in FIG. 5 show that while similarlevels of viral immediate-early gene ICP27 and early-late gene gD areexpressed in the presence and absence of tetracycline, no VP5 expressionwas detected in QREO5-F-infected cells in the absence of tetracycline,indicating that the lack of de novo synthesis of infectious QREO5-F inthe absence of tetracycline is the direct result of little or no VP5expression.

Doxycycline-dose dependent de novo viral production of QREO5-F. Tofinely assess the dependence of QREO5-F replication on the presence oftetracycline, H1299 cells were infected with QREO5-F at an MOI of 0.25PFU/cell in either the absence or presence of different concentration ofdoxycycline. Infected cells were harvested at 48 h post-infection (FIG.6 ). While the yield of QREO5-F at 48 h post-infection was 1.4×10⁷PFU/ml in the presence of 0.05 ug/ml of doxycycline, yield of QREO5-Fwas 0.33 PFU/ml in cells in the absence of doxycycline, indicating thatthe regulation of QREO5-F viral replication by doxycycline is close to5×10⁷-fold in infected H1299 cells.

Doxycycline-dependent replication of QREO5-F in cultured human tumorcells and primary cells. Having demonstrated that the replication ofQREO5-F is as productive as that of QREO5 in Vero cells and H1299 cells,the replicative and regulative abilities of QREO5-F in various humantumor cell lines were then investigated. As depicted in FIGS. 7A and 7B,QREO5-F infection of human breast, lung, ovary, pancreas, and skin tumorcell lines demonstrated that QREO5-F regulatability ranges from˜240,000-fold to ˜4×10⁷-fold, whereas the degree of QREO5-F regulationin human SNU-398 liver cancer cell line is about 36,000-fold.

To directly examine the onco-selectivity of QREO5-F in normal primaryhuman cells and human cancer cells, H1299 cells and dividing andnon-dividing human breast fibroblasts were infected with QREO5-F at anMOI of 0.25 PFU/cells in the presence and absence of tetracycline asdescribed by Yao et al. (2010). The results of FIG. 8A demonstrate thatreplication of QREO5-F in primary human fibroblasts, particularlynon-dividing fibroblasts, is markedly reduced compared with replicationin H1299 cells. Yields of QREO5-F at 72 h post-infection in H1299 cellswere more than 510,000-fold higher than those in the serum-starvedfibroblasts, and more than 160,000-fold higher than in fibroblasts grownin normal growth medium. Additionally, the cytotoxic effect of QREO5-Finfection in the presence of tetracycline was evaluated (FIG. 8B). Theresults show that QREO5-F exhibits little cytotoxic effect innon-dividing as well as dividing fibroblasts, and drastic cytotoxiceffect in H1299 cells (0.86% of infected cells remained viable). Thecorresponding morphological images of cells from the cytotoxicity assay(FIG. 8C) depict this cytopathic effect in H1299 (note the extensiveformation of syncytia). In contrast, very little or no cytotoxic effectsare visible among the infected or mock-infected human fibroblasts.Together, the results presented in FIG. 8 indicate that the ability ofQREO5-F to replicate in and kill normal primary human fibroblasts ismarkedly reduced relative to various human tumor cell lines.

Prevention and induction of tumor-specific immunity against the growthof pre-established CT26. WT tumor in immune-competent mice. Using asyngeneic CT26.WT colon cancer model in immuno-competent BALB/c mice(FIG. 9 ), it was shown herein that intratumoral inoculation of QREO5-Finto pre-established CT26.WT tumors lead to a markedly reduction inoverall tumor growth in QREO5-F treated tumors, of particular, in theQREO5-F treated tumor with local co-delivery of 1 ug of doxycycline.There was an average of 11.2-fold reduction in tumor volume inQREO5-F-treated tumor in the presence of doxycycline compared to that ofDMEM-treated group on day 21 post-QREO5-F virotherapy (p<0.001) (FIG.9A). Three mice in DMEM-treated group have to be euthanized on day 15post-initial intratumoral injection due to large tumor sizes. Theoverall tumor volume in QREO5-F-treated tumor in the presence ofdoxycycline was 2.4-fold lower than the QREO5-F-treated tumor in theabsence of local delivery of doxycycline. Importantly, QREO5-Fvirotherapy led to a 3.2-fold reduction in growth of the contralateraltumors that received no viruses compared to that of DMEM-treated mice(p<0.05) (FIG. 9B), indicating that intratumoral inoculation of QREO5-Fcan elicit an effective anti-tumor specific immunity that can limit thegrowth of disseminating tumors. Notably, three of 8 mice treated withQREO5-F plus local delivery of doxycycline were tumor free on bothflanks, while only one of 8 mice was tumor free in mice treated withQREO5-F without doxycycline. The described 4 QREO5-F cured mice remaintumor free on day 35 post first QREO5-F treatment.

To evaluate the induction of tumor-specific memory response followingQREO5-F treatment, 4 QREO5-F cured mice as well as 5 age-matched naïveBALB/c mice were re-challenged with CT26.WT cells. No any sign of tumorgrowth was detected in 4 QREO5-F cured mice, while all 5 naïve micedeveloped CT26.WT tumor with an average volume of about 1000 mm³ by day15 post-challenge (FIG. 10 ). Collectively, the results presented inFIGS. 9 and 10 strongly indicate that QREO5-F is very effective inprevention of the growth of pre-established CT26.WT tumor inimmuno-competent mice, and localized QREO5-F virotherapy is capable ofeliciting systemic immune response that can effectively prevent thegrowth of a distant tumor as well as CT26.WT tumor growth followingre-challenge with CT26.WT cells in immuno-competent mice.

Sequence analyses of QREO5-F genome. As expected, sequence analysis ofQREO5-F viral genome confirms that QREO5-F encodes tetR at the HSV-1ICP0 locus, and VP5 under the control of the tetO-containing VP5promoter. Unlike the first generation tet-regulatable oncolytic virusKTR27 (U.S. Pat. No. 8,236,941), which has both the ICP0 gene and theICP34.5 gene deleted, QREO5-F encodes wild-type ICP34.5 gene. Using theparental wild-type HSV-1 strain KOS genome as the reference, a total of53 missense mutations, and 3 frame shift mutations are identified in theQREO5-F genome. The UL36 gene of QREO5-F contains 12 missense mutationsand 2 frame shift mutations. Other missense mutations are located in theUL5 gene, the UL6 gene, the UL8 gene, the UL12 gene, UL21 gene, UL23gene, the UL25 gene, UL26 gene, the UL30 gene, the UL37 gene, the UL38gene, the UL39 gene, the UL40 gene, the UL44 gene, the UL52 gene, theUL53 gene (gK), the US1 gene, and the US8 gene. Because the UL5 geneencodes the DNA helicase, the UL8 gene encodes the primase, the UL12gene that encodes alkaline exonuclease, the UL23 gene that encodes TK,the UL30 gene encodes the catalytic subunit of the viral DNA polymerase,the UL39 gene encodes the large subunit of ribonucleotide reductase, theUL40 gene encodes the small subunit of ribonucleotide kinase, the UL52gene encodes the primase subunit of the HSV-1 helicase-primase complexand all these genes involve in viral DNA replication either directly orindirectly, it is reasonable to predict that some of these describedmutations further restrict the virus ability to replicate in normalcells than in cancer cells.

A single amino acid substitution, Ala to Thr at residue 40, isidentified in the gK gene of QREO5-F. The same Ala to Thr substitutionhas been identified in the HSV-1 syncytial mutants, syn20 (Dolter K E etal., J Virol 68:8277-8281, 1994), which was isolated from KOS-infectedhuman embryonic lung (HEL) cells in the presence of mutagens,N-methyl-N′-nitro-N-nitrosoguanidine (Read G S et al., J Virol35:105-113, 1980), indicating that the Ala to Thr substitution atresidue 40 of the gK gene in QREO5-F is a key factor for the observedfusogenic phenotype. Syncytial mutations in the gK gene also include Alato Val at residue 40 in the HSV-1 syncytial mutants, syn102, syn105 andsyn 33 (Dolter K E et al., J Virol 68:8277-8281, 1994), Asp to Asn atresidue 99 in syn31 and syn32, Leu to Pro at residue 304 in syn30, andArg to Leu at residue 310 (Dolter K E et al., J Virol 68:8277-8281,1994). No mutation is found in the gene encoding gB, the UL20 gene, andthe UL24 gene.

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SequencesSEQ ID NO: 1 is a nucleotide sequence that encodes QREO5-F LinearGenome (142,090 bp).GAGGAGCGGCTAGACCCCGGAAACGGGCCCCCCCCAAAACACACCCCCCGGGGGCGCGCGCGGCCCTTTAAAGGCGGGCGGCGGGCAGCCCGGGCCCCCCGCGGCCGCGACTAGCGAGTTAGACAGGCAAGCACTACTCGCCTCTGCACGCACATGCTTGCCTGTCAAACTCTACCACCCCGGCACGCTCTCTGTCTCCATGGCCCGCCGCCGCCATCGCGGCCCCCGCCGCCCCCGGCCGCCCGGGCCCACGGGCGCGGTCCCAACCGCACAGTCCCAGGTAACCTCCACGCCCAACTCGGAACCCGTGGTCAGGAGCGCGCCCGCGGCCGCCCCGCCGCCGCCCCCCGCCCCCCATTAGCATGCCCCTCCCGCCGACGCAACAGGGGCTTGGCCTGCGTCGGTGCCCCGGGGCTTCCCGCCTTCCCGAAGAAACTCATTACCATACCCGGAACCCCAGGGGACCAATGCGGGTTCATTGAGCGACCCGCGGGCCAATGCGCGAGGGGCCGTGTGTTCCGCCAAAAAAGCAATTAACATAACCCGGAACCCCAGGGGAGTGGTTACGCGCGGCGCGGGAGGCGGGGAATACCGGGGTTGCCCATTAAGGGCCGCGGGAATTGCCGGAAGCGGGAAGGGCGGCCGGGGCCGCCCATTAATGAGTTTCTAATTACCATCCGGGAAGCGGAACAAGGCCTCTGCAATTTTTTAATTCCCAGCCCGGGAAGGGGGCGGCCCGGCCCACTGGGCGGGGGTTACCGCCCAGTGGGCCGGGCCCCGACGACTCGGCGGACGCTGGTTGGCCGGGCCCCGCCGCGCTGGCGGCCGCCGATTGGCCAGTCCCGCCCTCCGAGGGCGGGCCCGCCTCGGGGGCGGGCCGGCTCCAAGCGTATATATGCGCGGCTCCTGCCATCGTCTCTCCGGAGAGCGGCTTGGTGCGGAGCTCCCGGGAGCTCCGCGGAAGACCCAGGCCGCCTCGGGTGTAACGTTAGACCGAGTTCGCCGGGCCGGCTCCGCGGGCCAGGGCCCGGGCACGGGCCTCGGGCCCCAGGCACGGCCCGATGACCGCCTCGGCCTCCGCCACCCGGCGCCGGAACCGAGCCCGGTCGGCCCGCTCGCGGGCCCACGAGCCGCGGCGCGCCAGGCGGGCGGCCGAGGCCCAGACCACCAGGTGGCGCACCCGGACGTGGGGCGAGAAGCGCACCCGCGTGGGGGTCGCGGGGGTCGCGGGGGTCGCGGGGGGCTTCGGCGCCCCCTCCCCGCCCGCGCGTCGCAGGCGCAGGCGCGCCAGGTGCTCTGCGGTGACGCGCAGGCGGAGGGCGAGGCGCGGCGGAAGGCGGAAGGGGGGAGGGGGGGTGGGAGGGGTTAGCCCCGCCCCCCGGGCCCGCGCCGGGCGGTGGGGACCGGGGGCGGGGGGCGGCGGCGGTGGGCCGGGCCTCTGGCGCCGGCTCGGGCGGGGGGCTGTCCGGCCAGTCGTCGTCGTCGTCGTCGGACGCGGACTCGGGAACGTGGAGCCACTGGCGCAGCAGCAGCGAACAAGAAGGCGGGGGCCCCTGGCGGGGGGCGGCGGCGGGGCGGCCGCGGGCGCGCTCCTGACCACGGGTTCCGAGTTGGGCGTGGAGGTTACCTGGGACTGGCGGTTGGGACCGCGCCCGTGGGCCCGGGCGGCCGGGGGCGGCGGGGGCCGCGATGGCGGCGGCGGGCCATGGAGACAGAGAGCGTGCCGGGGTGGTAGAGTTTGACAGGCAAGCATGTGCGTGCAGAGGCGAGTAGTGCTTGCCTGTCTAACTCGCTAGTCTCGGCCGGGGGGGGCCCGGGCTGCCCGCCGCCCGCCTTTAAAGGGCCGCGCGCCCCCCGCCAGTGGGCCCCCGCCTTCTTGTTCGCTGCTGCTGCGCCAGTGGCTCCACGTTCCCGAGTCCGCGTCCGACGACGACGACGACGACTGGCCGGACAGCCCCCCGCCCGAGCCGGCGCCAGAGGCCCGGCCCACCGCCGCCGCCCCCCGCCCCCGGTCCCCACCGCCCGGCGCGGGCCCGGGGGGCGGGGCTAACCCCTCCCACCCCCCCTCCGCCCCTTCCGCCTTCCGCCGCGCCTCGCCCTCCGCCTGCGCGTCACCGCCGAGCACCTGGCGCGCCTGCGCCTGCGACGCGCGGGCGGGGGGGGGCGCCGAAGCCCCCCCGACCCCCGCGACCCCCGCGACCCCCACGCGGGTGCGCTTCTCGCCCCACGTCCGGGTGCGCCACCTGGTGGTCTGGGCCTCGGCCGCCCGCCTGGCGCGCCGCGGCTCGTGGGCCCGCGAGCGGGCCGACCGGGCTCGGTTCCGGCGCCGGGTGGCGGAGGCCGAGGCGGTCATCGGGCCGGCCTGGGGCCCGAGGCCCGTGCCCGGGCCCGGCCCGCGGAGCCGGCCCGGCGAACTCGGTCTAACGTTACACCCGAGGCGGCCTGGGTCTTCCGCGGAGCTCCCGGGAGCTCCGCACCAAGCCGCTCTCCGGAGAGACGATGGCAGGAGCCGCGCATATATACGCTTGGAGCCGGCCCGCCCCCGAGGCGGGCCCGCCCTCGGAGGGCGGGACTGGCCAATCGGCGGCCGCCAGCGCGGCGGGGCCCGGCCAACCAGCGTCCGCCGAGTCGTCGGGGCCCGGCCCACTGGGCGGTAACTCCCGCCCAGTGGGCCGGGCCGCCCACTTCCCGGTATGGTAATTAAAAACTTGCAGAGGCCTTGTTCCGCTTCCCGGTATGGTAATTAGAAACTCATTAATGGGCGGCCCCGGCCGCCCTTCCCGCTTCCGGCAATTCCCGCGGCCCTTAATGGGCAACCCCGGTATTCCCCGCCTCCCGCGCCGCGCGTAACCACTCCCCTGGGGTTCCGGGTTATGTTAATTGCTTTTTTGGCGGAACACACGGCCCCTCGCGCATTGGCCCGCGGGTCGCTCAATGAACCCGCATTGGTCCCCTGGGGTTCCGGGTATGGTAATGAGTTTCTTCGGGAAGGCGGGAAGCCCCGGGGCACCGACGCAGGCCAAGCCCCTGTTGCGTCGGCGGGAGGGGCATGCTAATGGGGTTCTTTGGGGGACACCGGGTTGGTCCCCCAAATCGGGGGCCGGGCCGTGCATGCTAATGATATTCTTTGGGGGCGCCGGGTTGGTCCCCGGGGACGGGGCCGCTCCGCGGTGGGCCTGCCTCCCCTGGGACGCGCGGCCATTGGGGGAATCGTCACTGCCGCCCCTTTGGGGAGGGGAAAGGCGTGGGGTATAAGTTAGCCCTGGCCCGACGGTCTGGTCGCATTTGCACCTCGGCACTCGGAGCGAGACGCAGCAGCCAGGCAGACTCGGGCCGCCCCCTCTCCGCATCACCACAGAAGCCCCGCCTACGTTGCGACCCCCAGGGACCCTCCGTCAGCGACCCTCCAGCCGCATACGACCCCCCGGGGATCCTCTAGGGCCTCTGAGCTATTCCAGAAGTAGTGAAGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTCCGGATCGATCCTGAGAACTTCAGGGTGAGTTTGGGGACCCTTGATTGTTCTTTCTTTTTCGCTATTGTAAAATTCATGTTATATGGAGGGGGCAAAGTTTTCAGGGTGTTGTTTAGAATGGGAAGATGTCCCTTGTATCACCATGGACCCTCATGATAATTTTGTTTCTTTCACTTTCTACTCTGTTGACAACCATTGTCTCCTCTTATTTTCTTTTCATTTTCTGTAACTTTTTCGTTAAACTTTAGCTTGCATTTGTAACGAATTTTTAAATTCACTTTTGTTTATTTGTCAGATTGTAAGTACTTTCTCTAATCACTTTTTTTTCAAGGCAATCAGGGTATATTATATTGTACTTCAGCACAGTTTTAGAGAACAATTGTTATAATTAAATGATAAGGTAGAATATTTCTGCATATAAATTCTGGCTGGCGTGGAAATATTCTTATTGGTAGAAACAACTACATCCTGGTCATCATCCTGCCTTTCTCTTTATGGTTACAACGATATACACTGTTTGAGATGAGGATAAAATACTCTGAGTCCAAACCGGGCCCCTCTGCTAACCATGTTCATGCCTTCTTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGCTGTCTCATCATTTTGGCAAAGAATTGTAATACGACTCACTATAGGGCGAATTGATATGTCTAGATTAGATAAAAGTAAAGTGATTAACAGCGCATTAGAGCTGCTTAATGAGGTCGGAATCGAAGGTTTAACAACCCGTAAACTCGCCCAGAAGCTAGGTGTAGAGCAGCCTACATTGTATTGGCATGTAAAAAATAAGCGGGCTTTGCTCGACGCCTTAGCCATTGAGATGTTAGATAGGCACCATACTCACTTTTGCCCTTTAGAAGGGGAAAGCTGGCAAGATTTTTTACGTAATAACGCTAAAAGTTTTAGATGTGCTTTACTAAGTCATCGCGATGGAGCAAAAGTACATTTAGGTACACGGCCTACAGAAAAACAGTATGAAACTCTCGAAAATCAATTAGCCTTTTTATGCCAACAAGGTTTTTCACTAGAGAATGCATTATATGCACTCAGCGCTGTGGGGCATTTTACTTTAGGTTGTGTATTGGAAGATCAAGAGCATCAAGTCGCTAAAGAAGAAAGGGAAACACCTACTACTGATAGTATGCCGCCATTATTACGACAAGCTATCGAATTATTTGATCACCAAGGTGCAGAGCCAGCCTTCTTATTCGGCCTTGAATTGATCATATGCGGATTAGAAAAACAACTTAAATGTGAAAGTGGGTCCGCGTACAGCGGATCCCGGGAATTCAGATCTTATTAAAGCAGAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTTATCATGTCTGGTCGACCCGGGACGAGGGAAAACAATAAGGGACGCCCCCGTGTTTGTGGGGAGGGGGGGGTCGGGCGCTGGGTGGTCTCTGGCCGCGCCCACTACACCAGCCAATCCGTGTCGGGGAGGTGGAAAGTGAAAGACACGGGCACCACACACCAGCGGGTCTTTTGTGTTGGCCCTAATAAAAAAAACTCAGGGGATTTTTGCTGTCTGTTGGGAAATAAAGGTTTACTTTTGTATCTTTTCCCTGTCTGTGTTGGATGTATCGCGGGGGTGCGTGGGAGTGGGGGTGCGTGGGAGTGGGGGTGCGTGGGAGTGGGGGTGCGTGGGAGTGGGGGCCCACGCACCCCCACTCCCACGCACCCCCACACCCACGCACCCCCGCGATACATCCAACACAGACAGGGAAAAGATACAAAAGTAAACCTTTATTTCCCAACAGACAGCAAAAATCCCCTGAGTTTTTTTTATTAGGGCCAACACAAAAGACCCGCTGGTGTGTGGTGCCCGTGTCTTTCACTTTCCACCTCCCCGACACGGATTGGCTGGTGTAGTGGGCGCGGCCAGAGACCACCCAGCGCCCGACCCCCCCCTCCCCACAAACGGGGGGCCCGGAGAGCCGCGGCACCCGGACGCGCCCGGAAAGTCTTTCGCACCACCGGCGATCGGCACGGCCGCGCCCCCGCTTTTATAAAGGCTCAGATGACGCAGCAAAAACAGGCCACAGCACCACATGGGTAGGTGATGTAATTTTATTTTCCTCGTCTGCGGCCTAATGGATTTCCGGGCGCGGTGCCCCTGTCTGCAGAGCACTTAACGGATTGATATCTCGCGGGCACGCGCGCCCTTAATGGACCGGCGCGGGGCGGGGGGCCGGATACCCACACGGGCGGGGGGGGGTGTCGCGGGCCGTCTGCTGGCCCGCGGCCACATAAACAATGACTCGGGGCCTTTCTGCCTCTGCCGCTTGTGTGTGCGCGCGCCGGCTCTGCGGTGTCGGCGGCGGCGGCGGCGGTGGCCGCCGTGTTCGGTCTCGGTAGCCGGCCGGCGGGTGGACTCGCGGGGGGCCGGAGGGGGGGAGGCAGGGGGGGGGAGGGTGGGGATCAGGACTTCCACTTCCCGTCCTTCCATCCCCCGTTCCCCTCGGTTGTTCCTCGCCTCCCCCAACACCCCGCCGCTTTCCGTTGGGGTTGTTATTGTTGTCGGGATCGTGCGGGCCGGGGGTCGCCGGGGCAGGGGCGGGGGCGTGGGCGGGGGTGCTCGTCGATCGACCGGGCTCAGTGGGGGCGTGGGGTGGGTGGGAGAAGGCGAGGAGACTGGGGTGGGGGTGTCGGTGGGTGGTTGTTTTTTCCCCCCTGCCTTCCACCCTCCGGCCCCCCGCGAGTCCACCCGCCGGCCGGCTACCGAGACCGAACACGGCGGCCACCGCCGCCGCCGCCGCCGACACCGCAGAGCCGGCGCGCGCACACACAAGCGGCAGAGGCAGAAAGGCCCCGAGTCATTGTTTATGTGGCCGCGGGCCAGCAGACGGCCCGCGACACCCCCCCCCCCCCGTGTGGGGATCCGGCCCCCCGCCCCCGCCGCCCATTAAGGGCGCGCGTGCCCGCGGATATCATCCGTTAAGTGCTCTGCAGACAGGGGCACCGCGCCCGGAAATCCATTAGGCCGCAGACGAGGAAAATAAAATTACATCCCTACCCATGTGGTGCTGTGGCCTGTTTTTGCTGCGTCATCTGAGCCTTTATAAAAGCGGGGGCGCGGCCGTGCCGATCGCCGGTGGTGCGAAAGACTTTCCGGGCGCGTCCGGGCCCCCCGCCGCTAAACCCCATCCCGCCCCCGGGACCCCACATATAAGCCCCCAGCCACACGCAAGAACAGACACGCAGAACGGCTGTGTTTATTTTAAATAAACCGATGTCGGAATAAACAAACACAAACACCCGCGACGGGGGGACGGCGGGGACGGAGGGAGGGGGGGGACGGGGGACGGAAACAGACACAAAAAACAACCACAAAAAAAAAAAACAACCACCCACCGACACCCCCCCCCCAGTCTCCTCGCCTTCTCCCCCCACCCCACGCCCCCACTGAGCCCGGTCGATCGACGAGCACCCCCGCCCCCGCCCCCGCCCCTGCCCCGGCGACCCCCGGCCCGCACGATCCCGACAACAATAATCCGTCCCCCGTCCCCCCCTCCCTCCGTCCCCTCCGTCCCCCCTCGCGGGGGTTTGTGTTTGTTTATTCCGACATCGGTTTATTTAAAATAAACACAGCCGTTCTGCGTGTCTGTTCTTGCGTGTGGCTGGGGGCTTATATGTGGGGTCCCGGGGGCGGGATGGGGTTTAGCGGCGGGGGGCGGCGCGCCGGACGGGGCGCTGGAGATAGCGGCCCCCGGGGACCGGGGGACCGGGGCTGGGTATCCCGAGGTGGGGATGTGGGCGGGGGTGCGCGGGAGGGGTCGGTGGTGGGGGTGGTGGTGGTGGGGGTAGTAGGAATGGTGGGGGGGGGGAGGGCGCTGGTTGGTCAAAAAAGGGAGGGACGGGGGCCGGCAGACCGACGGCGACAACGCTCCCCGGCGGCCGGGTCGCGGCTCTTACGAGCGGCCCGGCCCGCGCTCCCACCCCCCGGGCCGTGTCCTTGCTTTCCCCCCGTCTCCCCCCCCGCCTTCTCCTCCTCCTCCTCGTTTTTCCAAACCCCGCCCACCCGGCCCGGCCCGGCCCGGCCCGGCCACCGCCGCCCACCCACCCACCTCGGGATACCCAGCCCCGGTCCCCCGTTCCCCGGGGGCCGTTATCTCCAGCGCCCCGTCCGGCGCGCCGCCCCCCGCCGCTAAACCCCATCCCGCCCCCGGGACCCCACATATAAGCCCCCAGCCACACGCAAGAACAGACACGCAGAACGGCTACGAGGAGGAGGAGGAGAAGGCGGGGGGGGAGACGGGGGGAAAGCAAGGACACGGCCCGGGGGGTGGGAGCGCGGGCCGGGCCGCTCGTAAGAGCCGCGACCCGGCCGCCGGGGAGCGTTGTCGCCGTCGGTCTGCCGGCCCCCGTCCCTCCCTTTTTTGACCAACCAGCGCCCTCCCCCCCGCGCGGGCCGGGCCGCTCGTAAGAGCCGCGACCCGGCCGCCGGGGAGCGTTGTCGCCGTCGGTCTGCCGGCCCCCGTCCCTCCCTTTTTTGACCAACCAGCGCCCTCCCCCCCACCACCATTCCTACTACCACCACCACCACCACCCCCACCACCGACACCTCCCGCGCACCCCCGCCCACATCCCCCCACCCCGCACCACGAGCACGGGGTGGGGGTAGCAGGGGATCAAAGGGGGGCAAAGCCGGCGGGGCGGTTCGGGGGGGCGGGAGACCGAGTAGGCCCGCCCATACGCGGCCCCTCCCGGCAGCCACGCCCCCCAGCGTCGGGTGTCACGGGGAAAGAGCAGGGGAGAGGGGGGGAGAGGGGAGAGGGGGGGAGAGGGGGTATATAAACCAACGAAAAGCGCGGGAACGGGGATACGGGGCTTGTGTGGCACGACGTCGTGGTTGTGTTACTGGGCAAACACTTGGGGACTGTAGGTTTCTGTGGGTGCCGACCCTAGGCGCTATGGGGATTTTGGGTTGGGTCGGGCTTATTGCCGTTGGGGTTTTGTGTGTGCGGGGGGGCTTGTCTTCAACCGAATATGTTATTCGGAGTCGGGTGGCTCGAGAGGTGGGGGATATATTAAAGGTGCCTTGTGTGCCGCTCCCGTCTGACGATCTTGATTGGCGTTACGAGACCCCCTCGGCTATAAACTATGCTTTGATAGACGGTATATTTTTGCGTTATCACTGTCCCGGATTGGACACGGTCTTGTGGGATAGGCATGCCCAGAAGGCATATTGGGTTAACCCCTTTTTATTTGTGGCGGGTTTTCTGGAGGACTTGAGTCACCCCGCGTTTCCTGCCAACACCCAGGAAACAGAAACGCGCTTGGCCCTTTATAAAGAGATACGCCAGGCGCTGGACAGTCGCAAGCAGGCCGCCAGCCACACACCTGTGAAGGCTGGGTGTGTGAACTTTGACTATTCGCGCACCCGCCGCTGTGTAGGGCGACAGGATTTGGGACCTACCAACGGAACGTCTGGACGGACCCCGGTTCTGCCGCCGGACGATGAAGCGGGCCTGCAACCGAAGCCCCTCACCACGCCGCCGCCCATCATCGCCACGTCGGACCCCACCCCGCGACGGGACGCCGCCACAAAAAGCAGACGCCGACGACCCCACTCCCGGCGCCTCTAACGATGCCTCGACGGAAACCCGTCCGGGTTCGGGGGGCGAACCGGCCGCCTGTCGCTCGTCAGGGCCGGCGGGCGCTCCTCGCCGCCCTAGAGGCTGTCCCGCTGGTGTGACGTTTTCCTCGTCCGCGCCCCCCGACCCTCCCATGGATTTAACAAACGGGGGGGTGTCGCCTGCGGCGACCTCGGCGCCTCTGGACTGGACCACGTTTCGGCGTGTGTTTCTGATCGACGACGCGTGGCGGCCCCTGATGGAGCCTGAGCTGGCGAACCCCTTAACCGCCCACCTCCTGGCCGAATATAATCGTCGGTGCCAGACCGAAGAGGTGCTGCCGCCGCGGGAGGATGTGTTTTCGTGGACTCGTTATTGCACCCCCGACGAGGTGCGCGTGGTTATCATCGGCCAGGACCCATATCACCACCCCGGCCAGGCGCACGGACTTGCGTTTAGCGTGCGCGCGAACGTGCCGCCTCCCCCGAGTCTTCGGAATGTCTTGGTGGCCGTCAAGAACTGTTATCCCGAGGCACGGATGAGCGGCCACGGTTGCCTGGAAAAGTGGGCGCGGGACGGCGTCCTGTTACTAAACACGACCCTGACCGTCAAGCGCGGGGCGGCGGCGTCCCACTCTAGAATCGGTTGGGACCGCTTCGTGGGCGGAGTTATCCGCCGGTTGGCCGCGCGCCGCCCCGGCCTGGTGTTTATGCTCTGGGGCGCACACGCCCAGAATGCCATCAGGCCGGACCCTCGGGTCCATTGCGTCCTCAAGTTTTCGCACCCGTCGCCCCTCTCCAAGGTTCCGTTCGGAACCTGCCAGCATTTCCTCGTGGCGAACCGATACCTCGAGACCCGGTCGATTTCACCCATCGACTGGTCGGTTTGAAAGGCATCGACGTCCGGGGTTTTTGTCGGTGGGGGCTTTTGGGTATTTCCGATGAATAAAGACGGTTAATGGTTAAACCTCTGGTCTCATACGGGTCGGTGATGTCGGGCGTCGGGGGAGAGGGAGTTCCCTCTGCGCTTGCGATTCTAGCCTCGTGGGGCTGGACGTTCGACACGCCAAACCACGAGTCGGGGATATCGCCAGATACGACTCCCGCAGATTCCATTCGGGGGGCCGCTGTGGCCTCACCTAACCAACCTTTACACGGGGGCCCGGAACGGGAGGCCACAGCGCCGTCTTTCTCCCCAACGCGCGCGGATGACGGCCCGCCCTGTACCGACGGGCCCTACGTGACGTTTGATACCCTGTTTATGGTGTCGTCGATCGACGAATTAGGGCGTCGCCAGCTCACGGACACCATCCGCAAGGACCTGCGGTTGTCGCTGGCCAAGTTTAGCATTGCGTGCACCAAGACCTCCTCGTTTTCGGGAAACGCCCCGCGCCACCACAGACGCGGGGCGTTCCAGCGCGGCACGCGGGCGCCGCGCAGCAACAAAAGCCTCCAGATGTTTGTGTTGTGCAAACGCGCCCACGCCGCTCGAGTGCGAGAGCAGCTTCGGGTCGTTATTCAGTCCCGCAAGCCGCGCAAGTATTACACGCGATCTTCGGACGGGCGGCTCTGCCCCGCCGTCCCCGTGTTCGTCCACGAGTTCGTCTCGTCCGAGCCAATGCGCCTCCACCGAGATAACGTCATGCTGGCCTCGGGGGCCGAGTAACCGCCCCCCCCCCCCCCCCGCCCCCCCCCCCCCCCCCCCCCCCCCCCTCCCCCCCCCCCCCCCCCTCTTCCCCCGTGACACCCGACGCTGGGGGGCGTGGCTGCCGGGAGGGGCCGCGTATGGGCGGGCCTACTCGGTCTCCCGCCCCCCCGAACCGCCCCGCCGGCTTTGCCCCCCGCGATCTTCGGACGGGCGGCTCTGCCCCGCCGTCCCCGTGTTCGTCCACGAGTTCGTCTCGTCCGAGCCAATGCGCCTCCACCGAGATAACGTCATGCTGGCCTCGGGGGCCGAGTAACCGCCCCCCCCCCATGCCACCCTCACTGCCCGTCGCGCGTGTTTGATGTTAATAAATAACACATAAATTTGGCTGGTTGTTTGTTGTCTTTAATGGACCGCCCGCAAGGGGGGGGGGGCGTTTCAGTGTCGGGTGACGAGCGCGATCCGGCCGGGATCCTAGGACCCCAAAAGTTTGTCTGCGTATTCCAGGGTGGGGCTCAGTTGAATCTCCCGCAGCACCTCTACCAGCAGGTCCGCGGTGGGCTGGAGAAACTCGGCCGTCCCGGGGCAGGCGGTTGTCGGGGGTGGAGGCGCGGCGCCCACCCCGTGTGCCGCGCCTGGCGTCTCCTCTGGGGGCGACCCGTAAATGGTTGCAGTGATGTAAATGGTGTCCGCGGTCCAGACCACGGTCAAAATGCCGGCCGTGGCGCTCCGGGCGCTTTCGCCGCGCGAGGAGCTGACCCAGGAGTCGAACGGATACGCGTACATATGGGCGTCCCACCCGCGTTCGAGCTTCTGGTTGCTGTCCCGGCCTATAAAGCGGTAGGCACAAAATTCGGCGCGACAGTCGATAATCACCAACAGCCCAATGGGGGTGTGCTGGATAACAACGCCTCCGCGCGGCAGGCGGTCCTGGCGCTCCCGGCCCCGTACCATGATCGCGCGGGTGCCGTACTCAAAAACATGCACCACCTGCGCGGCGTCGGGCAGTGCGCTGGTCAGCGAGGCCCTGGCGTGGCATAGGCTATACGCGATGGTCGTCTGTGGATTGGACATCTCGCGGTGGGTAGTGAGTCCCCCGGGCCGGGTTCGGTGGAACTGTAAGGGGACGGCGGGTTAATAGACAATGACCACGTTCGGATCGCGCAGAGCCGATAGTATGTGCTCACTAATGACGTCATCGCGCTCGTGGCGCTCCCGGAGCGGATTTAAGTTCATGCGAAGGAATTCGGAGGAGGTGGTGCGGGACATGGCCACGTACGCGCTGTTGAGGCGCAGGTTGCCGGGCGTAAAGCAGATGGCGACCTTGTCCAGGCTAAGGCCCTGGGAGCGCGTGATGGTCATGGCAAGCTTGGAGCTGATGCCGTAGTCGGCGTTTATGGCCATGGCCAGCTCCGTAGAGTCAATGGACTCGACAAACTCGCTGATGTTGGTGTTGACGACGGACATGAAGCCGTGTTGGTCCCGCAAGACCACGTAAGGCAGGGGGGCCTCTTCCAGTAACTCGGCCACGTTGGCCGTCGCGTGCCGCCTCCGCAGCTCGTCCGCAAAGGCAAACACCCGTGTGTACGTGTATCCCATGAGCGTATAATTGTCCGTCTGCAGGGCGACGGACATCAGCCCCCCGCGCGGCGAGCCGGTCAGCATCTCGCAGCCCCGGAAGATAACGTTGTCCACGTACGTGCTAAAGGGGGCGACTTCAAATGCCTCCCCGAAGAGCTCTTGGAGGATTCGGAATCTCCCGAGGAAGGCCCGCTTCAGCAGCGCAAACTGGGTGTGAACGGCGGCGGTGGTCTCCGGTTCCCCGGGGGTGTAGTGGCAGTAAAACACGTCGAGCTGTTGTTCGTCCAGCCCCGCGAAAATAACGTCGAGGTCGTCGTCGGGAAAATCGTCCGGGCCCCCGTCCCGCGGCCCCAGTTGCTTAAAATCAAACGCACGCTCGCCGGGGGCGCCTGCGTCGGCCATTACCGACGCCTGCGTCGGCACCCCCGAAGATTTGGGGCGCAGAGACAGAATCTCCGCCGTTAGTTCTCCCATGCGGGCGTACGCGAGGGTCCTCTGGGTCGCATCCAGGCCCGGGCGCTGCAGAAAGTTGTAAAAGGAGATAAGCCCGCTAAATATGAGCCGCGACAGGAACCTGTAGGCAAACTCCACCGAAGTCTCCCCCTGAGTCTTTACAAAGCTGTCGTCACGCAACACTGCCTCGAAGGCCCGGAACGTCCCACTAAACCCAAAAACCAGTTTTCGCAGGCGCGCGGTCACCGCGATCTGGCTGTTGAGGACGTAAGTGACGTCGTTGCGGGCCACGACCAGCTGCTGTTTGCTGTGCACCTCGCAGCGCATGTGCCCCGCGTCCTGGTCCTGGCTCTGCGAGTAGTTGGTGATGCGGCTGGTGTTGGCCGTGAGCCACTTTTCAATAGTCAGGCCGGGCTGGTGTGTCAGCCGTCGGTATTCGTCAAACTCCTTGACCGACACGAACGTAAGCACGGGGAGGGTTAACACGACGAACTCCCCCTCACGGGTCACCTTCAGGTAGGCGTGGAGCTTGGCCATGTACGCGCTCACCTCTTTGTGGGAGGAGAACAGCCGCGTCCAGCCGGGGAGGTTGGCGGGGTTGGTGATGTAGTTTTCCGGGACGACGAAGCGATCCACGAACTGCATGTGCTCCTCGGTGATGGGCAGGCCGTACTCCAGCACCTTCATGAGGTTACCGAACTCGTGCTCGACGCACCGTTTGTTGTTAATAAAAATGGCCCAGCTATACGAGAGGCGGGCGTACTCGCGCAGCGTGCGGGTGCAGATGAGGTACGTGAGCACGTTCTCGCTCTGGCGGACGGAACACCGCAGTTTCTGGTGCTCGAAGGCGACTCCAGGGACGCCGTCTGCGTCGGCGAGCCCACACACACCAACACGGGCCGCAGGCGGGCCGCGTACTGGGGGGTGTGGTACAGGGCGTTAATCATCCACCAGCAATACACCACGGCCGTGAGGAGGTGACGCCCAAGGAGCCCGGCCTCGTCGATGACGATCACGTTGCTGCGGGTAAAGGCCGGCAGCGCCCCGTGGGTGGCCGGGGCCAACCGCGTCAGGGCGCCCTCGGCCAACCCCAGGGTCCGTTCCAGGGCGGCCAGGGCGCGAAACTCGTTCCGCAACTCCTCGCCCCCGGAGGCGGCCAGGGCGCGCTTCGTGAGGTCCAAAATCACCTCCCAGTAGTACGTCAGATCTCGTCGCTGCAGGTCCTCCAGCGAGGCGGGGTTGCTGGTCAGGGTGTACGGGTACTGTCCCAGTTGGGCCTGGACGTGATTCCCGCGAAACCCAAATTCATGAAAGATGGTGTTGATGGGTCGGCTGAGAAAGGCGCCCGAGAGTTTGGCGTACATGTTTTGGGCCGCAATGCGCGTGGCGCCCGTCACCACACAGTCCAAGACCTCGTTGATTGTCTGCACGCACGTGCTCTTTCCGGAGCCAGCGTTGCCGGTGATAAGATACACCGCGAACGGAAACTCCCTGAGGGGCAGGCCTGCGGGGGACTCTAAGGCCGCCACGTCCCGGAACCACTGCAGACGGGGCACTTGCGCTCCGTCGAGCTGTTGTTGCGAGAGCTCTCGGATGCGCTTAAGGATTGGCTGCACCCCGTGCATAGACGTAAAATTTAAAAAGGCCTCGGCCCTCCCTGGAACGGCTGGTCGGTCCCCGGGTTGCTGAAGGTGCGGCGGGCCGGGTTTCTGTCCGTCTAGCTGGCGCTCCCCGCCGGCCGCCGCCATGACCGCACCACGCTCGTGGGCCCCCACTACGCGTGCGCGGGGGGACACGGAAGCGCTGTGCTCCCCCGAGGACGGCTGGGTAAAGGTTCACCCCACCCCCGGTACGATGCTGTTCCGTGAGATTCTCCACGGGCAGCTGGGGTATACCGAGGGCCAGGGGGTGTACAACGTCGTCCGGTCCAGCGAGGCGACCACCCGGCAGCTGCAGGCGGCGATCTTTCACGCGCTCCTCAACGCCACCACTTACCGGGACCTCGAGGCGGACTGGCTCGGCCACGTGGCGGCCCGCGGTCTGCAGCCCCAACGGCTGGTTCGCCGGTACAGGAACGCCCGGGAGGCGGATATCGCCGGGGTGGCCGAGCGGGTGTTCGACACGTGGCGGAACACGCTTAGGACGACGCTGCTGGACTTTGCCCACGGGTTGGTCGCCTGCTTTGCGCCGGGCGGCCCGAGCGGCCCGTCAAGCTTCCCCAAATATATCGACTGGCTGACGTGCCTGGGGCTGGTCCCCATATTACGCAAGCGACAAGAAGGGGGTGTGACGCAGGGTCTGAGGGCGTTTCTCAAGCAGCACCCGCTGACCCGCCAGCTGGCCACGGTCGCGGAGGCCGCGGAGCGCGCCGGCCCCGGGTTTTTTGAGCTGGCGCTGGCCTTCGACTCCACGCGCGTGGCGGACTACGACCGCGTGTATATCTACTACAACCACCGCCGGGGCGACTGGCTCGTGCGAGACCCCATCAGCGGGCAGCGCGGAGAATGTCTGGTGCTGTGGCCCCCCTTGTGGACCGGGGACCGTCTGGTCTTCGATTCGCCCGTCCAGCGGCTGTTTCCCGAGATCGTCGCGTGTCACTCCCTCCGGGAACACGCGCACGTCTGCCGGCTGCGCAATACCGCGTCCGTCAAGGTGCTGCTGGGGCGCAAGAGCGACAGCGAGCGCGGGGTGGCCGGTGCCGCGCGGGTCGTTAACAAGGTGTTGGGGGAGGACGACGAGACCAAGGCCGGGTCGGCCGCCTCGCGCCTCGTGCGGCTTATCATCAACATGAAGGGCATGCGCCACGTAGGCGACATTAACGACACCGTGCGTGCCTACCTCGACGAGGCCGGGGGGCACCTGATAGACGCCCCGGCCGTCGACGGTACCCTCCCTGGATTCGGCAAGGGCGGAAACAACCGCGGGTCTGCGGGCCAGGACCAGGGGGGGCGGGCGCCGCAGCTTCGCCAGGCCTTCCGCACGGCCGTGGTTAACAACATCAACGGCGTGTTGGAGGGCTATATAAATAACCTGTTTGGAACCATCGAGCGCCTGCGCGAGACCAACGCGGGCCTGGCGACCCAATTGCAGGAGCGCGACCGCGAGCTCCGGCGCGCAACAGCGGGGGCCCTGGAGCGCCAGCAGCGCGCGGCCGACCTGGCGGCCGAGTCCGTGACCGGTGGATGCGGCAGCCGCCCTGCGGGGGCGGACCTGCTCCGGGCCGACTATGACATTATCGACGTCAGCAAGTCCATGGACGACGACACGTACGTCGCCAACAGCTTTCAGCACCCGTACATCCCTTCGTACGCCCAGGACCTGGAGCGCCTGTCGCGCCTCTGGGAGCACGAGCTGGTGCGCTGTTTTAAAATTCTGTGTCACCGCAACAACCAGGGCCAAGAGACGTCGATCTCGTACTCCAGCGGGGCGATCGCCGCATTCGTCGCCCCCTACTTTGAGTCAGTGCTTCGGGCCCCCCGGGTAGGCGCGCCCATCACGGGCTCCGATGTCATCCTGGGGGAGGAGGAGTTATGGGATGCGGTTTTAAAAAACCCGCCTGCAAACGTACCTGACAGACATCGCGGCCCTGTTCGTCGCGGACGTCCAGCACGCAGCGCTGCCCCCGCCCCCCTCCCCGGTCGGCGCCGATTTCCGGCCCGGCGCGTCCCCGCGGGGCCGGTCCAGATCGCGGTCGCCCGGAAGAACTGCGCCAGGCGCGCCGGACCAGGGCGGGGGCATCGGGCACCGGGATGGCCGCCGCGACGGCCGACGATGAGGGGTCGGCCGCCACCATCCTCAAGCAGGCCATCGCCGGGGACCGCAGCCTGGTCGAGGCGGCCGAGGCGATTAGCCAGCAGACGCTGCTCCGCCTGGCCTGCGAGGTGCGCCAGGTCGGCGACCGCCAGCCGCGGTTTACCGCCACCAGCATCGCGCGCGTCGACGTCGCGCCTGGGTGCCGGTTGCGGTTCGTTCTGGACGGGAGTCCCGAGGACGCCTATGTGACGTCGGAGGATTACTTTAAGCGCTGCTGCGGCCAGTCCAGTTATCGCGGCTTCGCGGTGGCGGTCCTGACGGCCAACGAGGACCACGTGCACAGCCTGGCCGTGCCCCCCCTCGTTCTGCTGCACCGGTTCTCCCTGTTCAACCCCAGGGACCTCCTGGACTTTGAGCTTGCCTGTCTGCTGATGTACCTGGAGAACTGCCCCCGAAGCCACGCCACCCCGTCGACCTTTGCCAAGGTTCTGGCGTGGCTCGGGGTCGCGGGTCGCCGCACGTCCCCATTCGAACGCGTTCGCTGCCTTTTCCTCCGCAGTTGCCACTGGGTCCTAAACACACTCATGTTCATGGTGCACGTAAAACCGTTCGACGACGAGTTCGTCCTGCCCCACTGGTACATGGCCCGGTACCTGCTGGCCAACAACCCGCCCCCCGTTCTCTCGGCCCTGTTCTGTGCCACCCCGACGAGCTCCTCATTCCGGCTGCCGGGGCCGCCCCCCCGCTCCGACTGCGTGGCCTATAACCCCGCCGGGATCATGGGGAGCTGCTGGGCGTCGGAGGAGGTGCGCGCGCCTCTGGTCTATTGGTGGCTTTCGGAGACCCCAAAACGACAGACGTCGTCGCTGTTTTATCAGTTTTGTTGAATTTTAGGAAATAAACCCGGTTTTGTTTCTGTGGCCTCCCGACGGATGCGCGTGTCCTTCCTCCGTCTTGGTGGGTGGGTGTCTGTGTATCGCGTCCCATCTGTGCGGAGAGGGGGGGCATGTCGGCACGTATTCGGACAGACTCAAGCACACACGGGGGAGCGCTCTTGTCTCAGGGCAATGTTTTTATTGGTCAAACTCAGGCAAACAGAAACGACATCTTGTCGTCAAAGGGATACACAAACTTCCCCCCCTCTCCCCATACTCCCGCCAGCACCCCGGTAAACACCAACTCAATCTCGCGCAGGATTTCGCGCAGGTGATGAGCGCAGTCCACGGGGGGGAGCACAAGGGGCCGCGGGTATAGATCGACGGGGACGCCGACCGACTCCCCGCCTCCGGGACAGACACGCACGACGCGCCGCCAGTAGTGCTCTGCGTCCAGCAAGGCGCCGCCGCGGAAGGCAGTGGGGGGCAAGGGGTCGCTAGCCTCAAAGGGGGACACCCGAACGCTCCAGTACTCCGCGTCCAACCGTTTATTAAACGCGTCCACGATAAGGCGGTCGCAGGCGTCCTCCATAAGGCCCCGGGCCGTGAGTGCGTCCTCCTCCGGCACGCCTGCCGTTGTCAGGCCCAGGACCCGTCGCAGCGTGTCGCGTACGACCCCGGCCGCCGTGGTGTACGCGGGCCCGCGGAGAGGAAATCCCCCAAGATGGTCAGTGTTGTCGCGGGAGTTCCAGAACCACACTCCCGCCTGGTTCCAGGCGACTGCGTGGGTGTAGACGCCCTCGAGGGCCAGGCACAGTGGGTGCCGCAGCCGGAGGCCGTTGGCCCTAAGCACGGCTCCCACGGCCGTCTCGATGGCCCGCCGGGCGTCCTCGATCACCCCGGAAGCCGCATCCGCGTCTTGGGGGTCCACGTTAAAGACACCCCAGAACGCACCCCCATCGCCCCCGCAGACCGCGAACTTCACCGAGCTGGCCGTCTCCTCGATCTGCAGGCAGACGGCGGCCATTACCCCACCCAGGAGCTGCCGCAGCGCAGGGCAGGCGTCGCACGTGTCCGGGACCAGGCGCTCCAAGACGGCCCCGGCCCAGGGCTCTGAGGGAGCGGCCACCACCAGCGCGTCCAGTCTTGCTAGGCCCGTCCGGCCGTGGGGGTCCGCCAGCCCGCTCCCCCCGAGGTCGGCCAGGGCCACCAGGAGCTGGGCGCGAAGTCCGGGGAAGCAAAACCGCGCCGTCCAGACGGGCCCGACGGCCGCGGGCGGGTCTAACAGTTGGATGATTTTAGTGGCGGGATGCCACCGCGCCACCGCCTCCCGCACCGCGGGCAGGAGGCATCCGGCTGCCGCCGAGGCCACGCCGGGCCAGGCTCGCGGGGGGAGGACGACCCTGGCCCCCACCGCGGGCCAGGCCCCCAGGAGCGCGGCGTAAGCGGCCGCGGCCCCGCGCACCAGGTCCCGTGCCGACTCGGCCGTGGCCGGCACGGTGAACGTGGGCCAACCCGGAAACCCCAGGACGGCAAAGTACGGGACGGGTCCCCCCCGGACCTCAAACTCGGGCCCCAGAAAGGCAAAGACGGGGGCCAGGGCCCCGGGGGCGGCGTGGACCGTGGTATGCCACTGCCGGAAAAGGGCGACGAGCGCCGGCGCGGAGAACTTCTCGCCGGCGCTTACAAAGTAGTCGTAATCGCGGGGCAGCAGCACCCGTGCCGTGACTCGTTGCGGGTGCCCGCGTGGCCGCAGGCCCACCTCGCACACCTCGACCAGGTCCCCGAACGCGCCCTCCTTCTTGATCGGCGGAAACGCAAGAGTCTGGTATTCGCGCGCAAATAGCGCGGTTCCGGTGGTGATGTTAACGGTCAGCGAAGCGGCGGACGCGCACTGGGGGGTGTCGCGAATGGCCGCCAGGCGCGCCCACGCCAGCCGCGCGTCGGGATGCTCGGCAACGCGCGCCGCCAGGGCCATAGGGTCGATGTCAATGTTGGCCTCCGCGACCAGGAGAGCGGCGCGAGGGGCGGCGGGCGGGCCCCACGACGCTCTCTCAACTTTCACCACCAGTCCCGTGCGTGGGTCCGAGCCGATACGCAGCGGGGCGAACAGGGCCACCGGCCCGGTCTGGCGCTCCAGGGCCGCCAGGACGCACGCGTACAGCGCCCGCCACAGAGTCGGGTTCTCCAGGGGCTCCAGCGGGGAGGCGGCCGGCGTCGTCGCGGCGCGGGCGGCCGCCACGACGGCCTGGACGGAGACGTCCGCGGAGCCGTAGAAATCCCGCAGCTCCGTCGCGGTGACGGAGACCTCCGCAAAGCGCGCGCGACCCTCCCCTGCGGCGTTGCGACATACAAAATACACCAGGGCGTGGAAGTACTCGCGAGCGCGGGGGGGCAGCCATACCGCGTAAAGGGTAATGGCGCTGACGCTCTCCTCCACCCACACGATATCTGCGGTGTCCATCGCACGGCCCCTAAGGATCACGGGCGGTCTGTGGGTCCCATGCTGCCGTGCCTGGCCGGGCCCGGTGGGTCGCGGAAACCGGTGACGGGGGGGGGGCGGTTTTTGGGGTTGGGGTGGGGGTGGGAAACGGCCCGGGTCCGGGGGCCAACTTGGCCCCTCGGTGCGTTCCGGCAACAGCGCCGCCGGTCCGCGGACGACCACGTACCGAACGAGTGCGGTCCCGAGACTTATAGGGTGCTAAAGTTCACCGCCCCCTGCATCATGGGCCAGGCCTCGGTGGGGAGCTCCGACAGCGCCGCCTCCAGGATGATGTCAGCGTTGGGGTTGGCGCTGGATGAGTGCGTGCGCAAACAGCGCCCCCACGCAGGCACGCGTAGCTTGAAGCGCGCGCCCGCAAACTCCCGCTTGTGGGCCATAAGCAGGGCGTACAGCTGCCTGTGGGTCCGGCAGGCGCTGTGGTCGATGTGGTGGGCGTCCAACAACCCCACGATTGTCTGTTTGGTGAGGTTTTTAACGCGCCCCGCCCCGGGAAACGTCTGCGTGCTTTTGGCCATCTGCACGCCAAACAGTTCGCCCCAGATTATCTTGAACAGCGCCACCGCGTGGTCCGTCTCGCTAACGGACCCGCGCGGGGGACAGCCGCTTAGGGCGTCGGCGACGCGCTTGACGGCTTCCTCCGAGAGCAGAAGTCCGTCGGTTACGTTACAGTGGCCCAGTTCGAACACCAGCTGCATGTAGCGGTCGTAGTGGGGGGTCAGTAGGTCCAGCACGTCATCGGGGCCGAAGGTCCTCCCAGATCCCCCGGCCGCCGAGTCCCAATGCAGGCGCGCGGCCATGGTGCTGCACAGGCACAACAGCTCCCAGACGGGGGTTACGTTCAGGGTGGGGGGCAGGGCCACGAGCTCCAGCTCTCCGGTGACGTTGATCGTGGGGATGACGCCCGTGGCGTAGTGGTCATAGATCCGCCGAAATATGGCGCTGCTGCGGGTGGCCATGGGAACGCGGAGACAGGCCTCCAGCAACGCCAGGTAAATAAACCGCGTGCGTCCCATCAGGCTGTTGAGGTTGCGCATGAGCGCGACAATTTCCGCCGGCGCGACATCGGACCGGAGGTATTTTTCGACGAAAAGACCCACCTCCTCCGTCTCGGCGGCCTGGGCCGGCAGCGACGCCTCGGGATCCCGGCACCGCAGCTCCCGTAGATCGCGCTGGGCCCTGAGGGCGTCGAAATGTACGCCCCGCAAAAACAGACAGAAGTCCTTTGGGGTCAGGGTATCGTCGTGTCCCCAGAAGCGCACGCGTATGCAGTTTAGGGTCAGCAGCATGTGAAGGATGTTAAGGCTGTCCGAGAGACACGCCAGCGTGCATCTCTCAAAGTAGTGTTTGTAACGGAATTTGTTGTAGATGCGCGACCCCCGCCCCAGCGACGTGTCGCATGCCGACGCGTCACAGCGCCCCTTGAACCGGCGACACAGCAGGTTTGTGACCTGGGAGAACTGCGCGGGCCACTGGCCGCAGGAACTGACCACGTGATTAAGGAGCATGGGCGTAAAGACGGGCTCCGAGCGCGCCCCGGAGCCGTCCATGTAAATCAGTAGCTCCCCCTTGCGGAGGGTGCGCACCCGTCCCAGGGACTGGTACACGGACACCATGTCCGGTCCGTAGTTCATGGGTTTTACGTAGGCGAACATGCCATCAAAGTGCAGGGGATCGAAGCTGAGGCCCACGGTTACGACCGTCGTGTATATAACCACGCGGTATTGGCCCCACGTGGTCACGTCCCCGAGGGGGGTGAGCGAGTGAAGCAACAGCACGCGGTCCGTAAACTGACGGCAGAACCGGGCCACGATCTCCGCGAAGGAGACCGTCGACGAAAAAATGCAGATGTTATCGCCCCCGCCAAGGCGCGCTTCCAGCTCCCCAAAGAACGTGGCCCCCCGGGCGTCCGGAGAGGCGTCCGGAGACGGGCCGCTCGGCGGCCCGGGCGGGCGCAGGGCAGCCTGCAGGAGCTCGGTCCCCAGACGCGGGAGAAACAGGCACCGGCGCGCCGAAAACCCGGGCATGGCGTACTCGCCGACCACCACATGCACGTTTTTTTCGCCCCGGAGACCGCACAGGAAGTCCACCAACTGCGCGTTGGCGGTTGCGTCCATGGCGATGATCCGAGGACAGGTGCGCAGCAGGCGTAGCATTAACGCATCCACGCGGCCCAGTTGCTGCATCGTTGGCGAATAGAGCTGGCCCAGCGTCGACATAACCTCGTCCAGAACGAGGACGTCGTAGTTGTTCAGAAGGTTGGGGCCCACGCGATGAAGGCTTTCCACCTGGACGATAAGTCGGTGGAAGGGGCGGTCGTTCATAATGTAATTGGTGGATGAGAAGTAGGTGACAAAGTCGACCAGGCCTGACTCAGCGAACCGCGTCGCCAGGGTCTGGGTAAAACTCCGACGACAGGAGACGACGAGCACACTCGTGTCCGGAGAGTGGATCGCTTCCCGCAGCCAGCGGATCAGCGCGGTAGTTTTTCCCGACCCCATTGGCGCGCGGACCACAGTCACGCACCTGGCCGTCGGGGCGCTCGCGTTGGGGAAGGTGACGGGTCCGTGCTGCTGCCGCTCGATCGTTGTTTTCGGGTGAACCCGGGGCACCCATTCGGCCAAATCCCCCCCGTACAACATCCGCGCTAGCGATACGCTCGACGTGTACTGTTCGCACTCGTCGTCCCCAATGGGACGCCCGGCCCCCAGAGGATCTCCCGACTCCGCGCCCCCCACGAAAGGCATGACCGGGGCGCGGACGGCGTGGTGGGTCTGGTGTGTGCAGGTGGCGACGTTTGTGGTCTCTGCGGTCTGCGTCACGGGGCTCCTCGTCCTGGCCTCTGTGTTCCGGGCACGGTTTCCCTGCTTTTACGCCACGGCGAGCTCTTATGCCGGGGTGAACTCCACGGCCGAGGTGCGCGGGGGTGTAGCCGTGCCCCTCAGGTTGGACACGCAGAGCCTTGTGGGCACTTATGTAATCACGGCCGTGTTGTTGTTGGCCGCGGCCGTGTATGCCGTGGTCGGCGCCGTGACCTCCCGCTACGACCGCGCCCTGGACGCGGGCCGCCGTCTGGCTGCGGCCCGCATGGCCATGCCGCACGCCACGCTGATCGCCGGAAACGTCTGCTCTTGGTTGCTGCAGATCACCGTCCTGTTGCTGGCCCATCGCACCAGCCAGCTGGCCCACCTGGTTTACGTCCTGCACTTTGCGTGTCTGGTGTATTTTGCGGCCCATTTTTGCACCAGGGGGGTCCTGAGCGGGACGTATCTGCGTCAGGTGCACGGCCTGATGGAGCCGGCCCCGACTCATCATCGCGTCGTTGGCCCGGCTCGAGCCGTGCTGACAAACGCCTTGCTGTTGGGCGTCTTCCTGTGCACGGCCGACGCCGCGGTATCCCTGAATACCATCGCCGCGTTCAACTTTAATTTTTCGGCCCCGGGCATGCTCATATGCCTGACCGTGCTGTTCGCCCTTCTCGTCGTATCGCTGTTGTTGGTGGTCGAGGGGGTGTTGTGTCACTACGTGCGCGTGTTGGTGGGCCCCCACCTGGGGGCCGTGGCCGCCACGGGCATCGTCGGCCTGGCATGCGAGCACTATTACACCAACGGCTACTACGTIGTGGAGACGCAGTGGCCGGGGGCCCAGACGGGAGTCCGCGTCGCCCTCGCCCTGGTCGCCGCCTTTGCCCTCGGCATGGCCGTGCTCCGCTGCACCCGCGCCTATCTGTATCACAGGCGGCACCACACCAAATTTTTTATGCGCATGCGCGACACGCGACACCGCGCACATTCCGCCCTCAAGCGCGTACGCAGTTCCATGCGCGGATCGCGAGACGGCCGCCACAGGCCCGCACCCGGCAGCCCGCCCGGGATTCCCGAATATGCGGAAGACCCCTACGCGATCTCATACGGCGGCCAGCTCGACCGGTACGGAGATTCCGACGGGGAGCCGATTTACGACGAGGTGGCGGACGACCAAACCGACGTATTGTACGCCAAGATACAACACCCGCGGCACCTGCCCGACGACGAGCCCATCTATGACACCGTTGGGGGGTACGACCCCGAGCCCGCCGAGGACCCCGTGTACAGCACCGTCCGCCGTTGGTAGCTGITTGGTTCCGTTTTAATAAACCGTTTGTGTTTAACCCGACCGTGGTGTATGTCTGGTGTGTGGCGTCCGATCCCGTTACTATCACCGTTCCCCCCAAACCCCGGCGATTGTGGGTTTTTTTAAAAACGACACGCGTGCGACCGTATACAGAACATTGTTGTTTTTTATTCGCTATCGGACATGGGGGGTGGAAACTGGGTGGCGGGGCAGGCGCCTCCGGGGGTTCGCCGGTGAGTGTGGCGCGAGGGGGGATCCGACGAACGCAGGCGCTGTCTCCCCGGGGCCCGCGTAACCCCGCGCATATCCGGGGGCACGTAGAAATTACCTTCCTCTTCGGACTCGATATCCACGACGTCAAAGTCGTGGGCGGTCAGCGAGACGACCTCCCCGTCGTCGGTGATGAGGACGTTGTTTCGGCAGCAGCAGGGCCGGGTCCCGGAGAACGAGAGGCCCATAGCTCGGCGAGCGTGTCGTCGAACGCCAGGCGGCTGCTTCGCTGTATGGCCTTATAGATCTCCGGATCGATGCGGACGGGGGTAATGATCAGGGCGATCGGAACGGCCTGGTTCGGGAGAATGGACGCCTTGCTGGGTCCTGCGGCCCCGAGAGCCCCGGCGCCGTCCTCCAGGCGGAACGTTACGCCCTCCTCCGCGCTAGTGCGGTGCCTGCCGATAAACGTCACCAGATGCGGGTGGGGGGGGCAGTCGGGGAAGTGGCTGTCGAGCACGTAGCCCTGCACCAAGATCTGCTTAAAGTTCGGGTGACGGGGGTTCGCGAAGACGGGCTCGCGGCGTACCAGATCCCCGGAGCTCCAGGACACGGGGGAGATGGTGTGGCGTCCGAGGTCGGGGGTGCCAAACAGAAGCACCTCCGAGACAACGCCGCTATTTAACTCCACCAAGGCCCGATCCGCGGCGGAGCACCGCCTTTTTTCGCCCGAGGCGTGGGCCTCTGACCAGGCCTGGTCTTGCGTGACGAGAGCCTCCTCCGGGCCGGGGACGCGCCCGGGCGCGAAGTATCGCACGCTGGGCTTCGGGATCGACCGGATAAATGCCCGGAACGCCTCCGGGGACCGGTGTGCCATCAAGTCCTCGTACGCGGAGGCCGTGGGGTCGCTGGGGTCCATGGGGTCGAAAGCGTACTTGGCCCGGCATTTGACCTCGTAAAAGGCCAGGGGGGTCTTGGGGACTGGGGCCAAGTAGCCGTGAATGTCCCGAGGACAGACGAGAATATCCAGGGACGCCCCGACCATCCCCGTGTGACCGTCCATGAGGACCCCACACGTATGCACGTTCTCTTCGGCGAGGTCGCCGGGTTCGTGGAAGATAAAGCGCCGCGTGTCGGCGCCGGCCTCGCCGCCGTCGTCCGCGCGGCCCACGCAGTAGCGAAACAGCAGGCTTCGGGCCGTCGGCTCGTTCACCCGCCCGAACATCACCGCCGAAGACTGTACATCCGGCCGCAGGCTGGCGTTGTGCTTCAGCCACTGGGGCGAGAAACACGGACCCTGGGGGCCCCAGCGGAGGGTGGATGCGGTCGTGAGGCCCCGCCGGAGCAGGGCCCATAGCTGGCAGTCGGCCTGGTTTTGCGTGGCCGCCTCGTAAAACCCCATGAGGGGCCGGGGCGCCACGGCGTCCGCGGCGGCCGGGGGCCCGCGGCGCGTCAGGCGCCATAGGTGCCGGCCGAGTCCGCGGTCCACCATACCCGCCTCCTCGAGGACCACGGCCAGGGAACACAGATAATCCAGGCGGGCCCAGAGGGGACCGATGGCCAGAGGGGCGCGGACGCCGCGCAGCAACCCGCGCAGGGGCGCTCGAACGTCTCGGCTAGTATATGGGAGGGCAGCGCGTTGGGGATCACCGACGCCGACCACATAGAGTCAAGGTCCGGGGAGTCGGGATCGGCGTCCGGGTCGCGGGCGTGGGTGCCCCCAGGAGATAGCGGAATGTCTGGGGTCGGAGGCCCTGAGGCGTCAGAAAGTGCCGGCGACGCGGCCCGGGGCTTTTCGTCTGCGGTGTCGGTGGCGTGCTGATCACGTGGGGGGTTAACGGGCGAATGGGAGCTCGGGTCCACAACTGACGTCGTCTGGGGTGGGGGGGGCAGGGGACGGAAGGTGGTTGTTAGCGGAAGACTGTTAGGGCGGGGGCGCTTGGGGGGGCTGTCGGGGCCACGAGGGGTGTCCTCGGCCAGGGCCCAGGAACGCTTAGTCACGGTGCGTCCCGGCGGACATGCTGGGCCTCCCGTGGACTCCATTTCCGAGACGACGTGGGGGGAGCGGTGGTTGAGCGCGCCGCCGGGTGAACGCTGATTCTCACGACAGCGCGTGCCGCGCGCACGGGTTGGTGTGACACAGGCGGGACACCAGCACCAGGAGAGGCTTAAGCTCGGGAGGCAGCGCCACCGACGACAGTATCGCCTTGTGTGTGTGCTGGTAATTTATACACCGATCCGTAAACGCGCGCCGAATCTTGGGATTGCGGAGGTGGCGCCGGATGCCCTCTGGGACGTCATACGCCAGGCCGTGGGTGTTGGTCTCGGCCGAGTTGACAAACAGGGCTGGGTGCAGCACGCGGCGATAGGCGAGCAGGGCCAGGGCGAAGTCCAGCGACAGCTGGTTGTTGAAATACTGGTAACCGGGAAACCGGGTCACGGGTACGCCCAGGCTCGGGGCGACGTACACGCTAACCACCAACTCCAGCAGCGTCTGGCCAAGGGCGTACAGGTCAACCGCTAACCCGACGTCGTGCTTCAGGCGGTGGTTGGTAAATTCGGCCCGTTCGTTGTTAAGGTATTTCACCAACAGCTCCGGGGGCTGGTTATACCCGTGACCCACCAGGGTGTGAAAGTTGGCTGTGGTTAGGGCGGTGGGCATGCCAAACATCCGGGGGGACTTGAGGTCCGGCTCCTGGAGGCAAAACTGCCCCCGGGCGATCGTGGAGTTGGAGTTGAGGGTGACGAGGCTAAAGTCGGCGAGGACGGCCCGCCGGAGCGAGACGGCGTCCGACCGCAGCATGACGAGGATGTTGGCGCACTTGATATCCAGGTGGCTGATCCCGCAGGTGGTGTTTAAAAACACAACGGCGCGGGCCAGCTCCGTGAAGCACTGGTGGAGGGCCGTCGAGACCGAGGGGTTTGTTGTGCGCAGGGACGCCAGTTGGCCGATATACTTACCGAGGTCCATGTCGTACGCGGGGAACACTATCTGTCGTTGTTGCAGCGAGAACCCGAGGGGCGCGATGAAGCCGCGGATGTTGTGGGTGCGGCCGGCGCGTAGAGCGCACTCCCCGACCAACAGGGTCGCGATGAGCTCAACGGCAAACCACTCCTTTTCCTTTATGGTCTTAACGGCAAGCTTATGTTCGCGAATCAGTTGGACGTCGCCGTATCCCCCAGACCCCCCGAAGCTTCGGGCCCCGGGGATCTCGAGGGTCGTGTAGTGTAGGGCGGGGTTGATGGCGAACACGGGGCTGCATAGCTTGCGGATGCGCGTGAGGGTAAGGATGTGCGAGGGGGACGAGGGGGGTGCGGTTAACGCCGCCTGGGATCTGCGCAGGGGCGGGCGGTTCAGTTTGGCCGCCGTACCGGGCGTCTCGGGGGACGCGCGGCGATGAGACGAGCGGCTCATTCGCCATCGGGATAGTCCCGCGCGAAGCCGCTCGCGGAGGCCGGATCGGTGGCGGGACCCGTGGGAGGAGCGGGAGCCGGCGGCGTCCTGGAGAGAGGGGCCGCTGGGGCGCCCGGAGGCCCCGTGTGGGTTGGAGTGTATGTAGGATGCGAGCCAATCCTTGAAGGACTGTTGGCGTGCACCTTGGGGGCTGAGGTTAGCTGCCACATGACCAGCAGGTCGCTGTCTGCGGGACTCATCCATCCTTCGGCCAGGTCGCCGTCTTCCCACAGAGAAGCGTTGGTCGCTGCTTCCTCGAGTTGCTCCTCCTGGTCCGCAAGACGATCGTCCACGGCGTCCAGGCGCTCACCAAGCGCCGGATCGAGGTACCGTCGGTGTGCGGTTAGAAAGTCACGACGCGCCGCTTGCTCCTCCACGCGAATTTTAACACAGGTCGCGCGCTGTCGCATCATCTCTAAGCGCGCGCGGGACTTTAGCCGCGCCTCCAATTCCAAGTGGGCCGCCTTTGCAGCCATAAAGGCGCCAACAAACCGAGGATCTTGGGTGCTGACGCCCTCCCGGTGCAGCTGCAGGGTCTGGTCCTTGTAAATCTCGGCTCGGAGGTGCGTCTCGGCCAGGCGTCGGCGCAGGGCCGCGTGGGCGGCATCTCGGTCCATTCCGCCACCCTGCGGGCGACCCGGGGGGTGCTCTGATAGTCTCGCGTGCCCAAGGCCCGTGATCGGGGTACTTCGCCGCCGCGACCCGCCACCCGGTGTGCGCGATGTTTGGTCAGCAGCTGGCGTCCGACGTCCAGCAGTACCTGGAGCGCCTCGAGAAACAGAGGCAACTTAAGGTGGGCGCGGACGAGGCGTCGGCGGGCCTCACAATGGGCGGCGATGCCCTACGAGTGCCCTTTTTAGATTTCGCGACCGCGACCCCCAAGCGCCACCAGACCGTGGTCCCGGGCGTCGGGACGCTCCACGACTGCTGCGAGCACTCGCCGCTCTTCTCGGCCGTGGCGCGGCGGCTGCTGTTTAATAGCCTGGTGCCGGCGCAACTAAAGGGGCGTGATTTCGGGGGCGACCACACGGCCAAGCTGGAATTCCTGGCCCCCGAGTTGGTACGGGCGGTGGCGCGACTGCGGTTTAAGGAGTGCGCGCCGGCGGACGTGGTGCCTCAGCGTAACGCCTACTATAGCGTTCTGAACACGTTTCAGGCCCTCCACCGCTCCGAAGCCTTTCGCCAGCTGGTGCACTTTGTGCGGGACTTTGCCCAGCTGCTTAAAACCTCCTTCCGGGCCTCCAGCCTCACGGAGACCACGGGCCCCCCAAAAAAACGGGCCAAGGTGGACGTGGCCACCCACGGCCGGACGTACGGCACGCTGGAGCTGTTCCAAAAAATGATCCTTATGCACGCCACCTACTTTCTGGCCGCCGTGCTCCTCGGGGACCACGCGGAGCAGGTCAACACGTTCCTGCGTCTCGTGTTTGAGATCCCCCTGTTTAGCGACGCGGCCGTGCGCCACTTCCGCCAGCGCGCCACCGTGTTTCTCGTCCCCCGGCGCCACGGCAAGACCTGGTTTCTAGTGCCCCTCATCGCGCTGTCGCTGGCCTCCTTTCGGGGGATCAAGATCGGCTACACGGCGCACATCCGCAAGGCGACCGAGCCGGTGTTTGAGGAGATCGACGCCTGCCTGCGGGGCTGGTTCGGTTCGGCCCGAGTGGACCACGTTAAAGGGGAAACCATCTCCTTCTCGTTTCCGGACGGGTCGCGCAGTACCATCGTGTTTGCCTCCAGCCACAACACAAACGTAAGTCCTCTTTTCTTTCGCATGGCTCTCCCAAGGGGCCCCGGGTCGACCCGACCCACACCCACCCACCCACCCACATACACACACAACCAGACGCGGGAGGAAAGTCTGCCCCGTGGGCACTGATTTTTATTCGGGATCGCTTGAGGAGGCCCGGGCAACGGCCCGGGCAACGGTGGGGCAACTCGTAGCAAATAGGCGACTGATGTACGAAGAGAAGACACACAGGCGCCACCCGGCGCTGGTCGGGGGGATGTTGTCCGCGCCGCACCGTCCCCCGACGACCTCTTGCAGACGGTCCGTGATGCAAGGACGGCGGGGGGCCTGCAGCAGGGTGACCGTATCCACGGGATGGCCAAAGAGAAGCGGACACAGGCTAGCATCCCCCTGGACCGCCAGGGTACACTGGGCCATCTTGGCCCACAGACACGGGGCGACGCAGGGACAGGACTCCGTTACGACGGAGGAGAGCCACAGTGCGTTGGCGGAATCGATGTGGGGCGGCGGGGCGCAGGACTCGCAGCCCCCCGGGTGGTTGGTGATCCTGGCCAGGAGCCATCCCAGATGGCGGGCCCTGCTTCCCGGTGGACAGAGCGACCCCAGGTCGCTGTCCATGGCCCAGCAGTAGATCTGGCCGCTGGGGAGGTGCCACCAGGCCCCCGGGCCCAAGGCGCAACACGCGCCCGGCTCCGGGGGGGTCTTCGCGGGGACCAGATACGCGCCATCCAGCTCGCCGACCACTGGCTCCTCCGCGAGCTGTTCGGTGGTTGGGTCGGGGGTTTCCTCCGGGGGGGTGGCCGCCCGTATGCGGGCGAACGTGAGGGTGCACAGGAGCGGGGTCAGGGGGTGCGTCACGCTCCGGAGGTGGACGATCGCGCAGTAGCGGCGCTCGCGGTTAAAGAAAAAGAGGGCAAAGAAGGTGTTCGGGGGCAACCGCAGCGCCTTGGGGCGCGTCAGATACAGAAAAATCTCGCAGAAGAGGGCGCGCCCGGGGTCTGGGTTAGGAAGGGCCACCTGACACAGAGGCTCGGTGAGGACCGTTAGACACCGAAAGATCTTGAGCCGCTCGTCCGCCCGAACGACGCGCCACACAAAGACGGAGTTGACAATGCGCGCGATAGAGTCGACGTCCGTCCCCAGGTCGTCGACTCTGTCGCGCGTGCCGCGAGCTCCGGCCCGGGAATCCGGCCGGGGCAAGGTCCCCGGGGGACCAGGCGGCGCCAGGGGCCGCCGGGGTCCCAGCTGCGCCATGCCGGGGGCGGGGGGAGGGCAAACCCCAGAGGCGGGGGCCAACGGCGCGGGGAGGAGTGGGTGGGCGAGGTGGCCGGGGGAAGGCGCCCGCTAGCGAGAACGGCCGTTCCCGGACGACACCTTGCGACAAAACCTAAGGACAGCGGCCCGCGCGACGGGGTCCGAGAGGCTAAGGTAGGCCGCGATGTTAATGGTGAACGCAAAGCCGCCGGGAAAGACAACTATGCCACAGAGGCGGCGATTAAACCCCAGGCAGAGGTAGGCGTAGCTTTCCCCGGGCAGGTATTGCTCGCAGACCCTGCGTGGGGCTGTGGAGGGGACGGCCTCCATGAAGCGACATTTACTCTGCTCGCGTTTACTGACGTCACCATCCATCGCCACGGCGATTGGACGATTGTTAAGCCGCAGCGTGTCTCCGCTTGTGCTGTAGTAGTCAAAAACGTAATGGCCGTCGGAGTCGGCAAAGCGGGCCGGGAGGTCGTCGCCGAGCGGGACGACCCGCCGCCCCCGACCGCCCCGTCCCCCCAGGTGTGCCAGGACGGCCAGGGCATACGCGGTGTGAAAAAAGGCGTCGGGGGCGGTCCCCTCGACGGCGCGCATCAGGTTCTCGAGGAGAATGGGGAAGCGCCTGGTCACCTCCCCCAGCCACGCGCGTTGGTCGGGGCCAAAGTCATAGCGCAGGCGCTGTGAGATTCGAGGGCCGCCCTGAAGCGCGGCCCGGATGGCCTGGCCCAGGGCCCGGAGGCACGCCAGATGTATGCGCGCAGTAAAGGCGACCTCGGCGGCGATGTCAAAGGGCGGCAGGACGGGGCGCGGGTGGCGCAGGGGCACCTCGAGCGCGGGAAAGCGGAGCAGCAGCTCCGCCTGCCCAGCGGGAGACAGCTGGTGGGGGCGCACGACGCGTTCTGCGGCGCAGGCCTCGGTCAGGGCCGTGGCCAGCGCCGAGGACAGCAGCGGGGGCGGGCGCGTCGCCCGCCCCACGCCACGGAGTTCTCGTAGGAGACGACGACGAAGCGCTGCTTGGTTCCGTAGTGGTGGCGCAGGACCACGGAGATAGAACGACGGCTCCACAGCCAGTCCGGCCGGTCGCCGCCGGCCAGGGCTTCCCATCCGCGATCCAACCACTCGACCAGCGACCGCGGCTTTGCGGTACCAGGGGTCAGGGTTAGAACGTCGTTCAGGATGTCCTCGCCCCCGGGCCCGTGGGGCACTGGGGCCACAAAGCGGCCCCCGCCTGGGGGCTCCAGACCCGCCAACACCGCATCTGCGTCAGCCGCCCCCATGGCGCCCCCGCTGACGGCCTGGTGAACCAGGGCGCCCTGGCGGAGCCCCGATGCAACGCCACAGGCCGCACGCCCGGTCCGAGCGCGGACCGGGTGGCGGCGGGTGACGTCCTGCACTGCCCGCTGAACCAACGCGAGGATCTCCTCGTTCTCCTGCGCGATGGACACGTCCTGGGCCGCGGTCGTGTCGCCGCCGGGGGCCGTCAGCTGCTCCTCCGGGGAGATGGGGGGGTCGGACGCCCCGACGATGGGCGGGTCTGCGGGCGCCCCCGCGTGGGGCCGGGCCAAGGGCTGCGGACGCGGGGACGCGCTTTCCCCCAGACCCATGGACAGGTGGGCCGCAGCCTCCTTCGCGGCCGGCGGGGCGGCGGCGCCAAGCAGAGCGACGTAGCGGCACAAATGCCGACAGACGCGCATGATGCGCGTGCTGTCGGCCGCGTAGCGCGTGTTGGGGGGGACGAGCTCGTCGTAACTAAACAGAATCACGCGGGCACAGCTCGCCCCCGAGCCCCACGCAAGGCGCAGCGCCGCCACGGCGTACGGGTCATAGACGCCCTGTGCGTCACACACCACGGGCAAGGAGACGAACAACCCCCCGGCGCTGGACGCACGCGGAAGGAGGCCAGGGTGTGCCGGCACGACGGGGGCCAGAAGCTCCCCCACCGCATCCGCGGGCACGTAGGCGGCAAACGCCGTGCACCACGGGGTACAGTCGCCGGTGGCATGAGCCCGAGTCTGGATTTCGACCTGGAAGTTTGCGGCCGTCCCGAGTCCGGGGCGGCCGCGCATCAGGGCGGCCAGAGGGATTCCCGCGGCCGCCAGGCACTCGCTGGATATGATGACGTGAACCAAAGACGAGGGCCGACCCGGGACGTGGCCGAGATCGTACTGGACCTCGTTGGCCAAGTGCGCGTTCATGGTTCGGGGGTGGGTGTGGGTGTGTAGGCGATGCGGGTCCCCCGAGTCCGCGGGAAGGGCGCGGGTTTGGCGCGCGTATGCGTATTCGCCAACGGAGGCGTGCGTGCTTATGCGCGGCGCGTTTCTTCTGTCTCCAGGGAATCCGAGGCCAGGACTTTAACCTGCTCTTTGTCGACGAGGCCAACTTTATTCGCCCGGATGCGGTCCAGACGATTATGGGCTTTCTCAACCAGGCCAACTGCAAGATTATCTTCGTGTCGTCCACCAACACCGGGAAGGCCAGTACGAGCTTTTTGTACAACCTCCGCGGGGCCGCCGACGAGCTTCTCAACGTGGTGACCTATATATGCGATGATCACATGCCGCGGGTGGTGACGCACACAAACGCCACGGCCTGTTCTTGTTATATCCTCAACAAGCCCGTTTTCATCACGATGGACGGGGCGGTTCGCCGGACCGCCGATTTGTTTCTGGCCGATTCCTTCATGCAGGAGATCATCGGGGGCCAGGCCAGGGAGACCGGCGACGACCGGCCCGTTCTGACCAAGTCTGCGGGGGAGCGGTTTCTGTTGTACCGCCCCTCGACCACCACCAACAGCGGCCTCATGGCCCCCGATTTGTACGTGTACGTGGATCCCGCGTTCACGGCCAACACCCGAGCCTCCGGGACCGGCGTCGCTGTCGTCGGGCGGTACCGCGACGATTATATCATCTTCGCCCTGGAGCACTTTTTTCTCCGCGCGCTCACGGGCTCGGCCCCCGCCGACATCGCCCGCTGCGTCGTCCACAGTCTGACGCAGGTCCTGGCCCTGCATCCCGGGGCGTTTCGCGGCGTCCGGGTGGCGGTCGAGGGAAATAGCAGCCAGGACTCGGCCGTCGCCATCGCCACGCACGTGCACACAGAGATGCACCGCCTACTGGCCTCGGAGGGGGCCGACGCGGGCTCGGGCCCCGAGCTTCTCTTCTACCACTGCGAGCCTCCCGGGAGCGCGGTGCTGTACCCCTTTTTCCTGCTCAACAAACAGAAGACGCCCGCCTTTGAACACTTTATTAAAAAGTTTAACTCCGGGGGCGTCATGGCCTCCCAGGAGATCGTTTCCGCGACGGTGCGCCTGCAGACCGACCCGGTCGAGTATCTGCTCGAGCAGCTGAATAACCTCACCGAAACCGTCTCCCCCAACACGGACGTCCGTACGTATTCCGGAAAACGGAACGGCGCCTCGGATGACCTTATGGTCGCCGTCATTATGGCCATCTACCTTGCGGCCCAGGCCGGACCTCCGCACACATTCGCTCCCATCACACGCGTTTCGTGAGCGCCCAATAAACACACCCAGGTATGCTACGCACGACCACGGTGTCGCCTGTTAAGGGGGGGGGAAGGGGGTGTTGGCGGGAAGCGTGGGAACACGGGGGATTCTCTCACGACCGGCACCAGTACCACCCCCCTGTGAACACAGAAACCCCAACCCAAATCCCATAAACATACGACACACAGGCATATTTTGGAATTTCTTAGGTTTTTATTTATTTAGGTATGCTGGGGTTTCTCCCTGGATGCCCACCCCCACCCCCCCCCGTGGGTCTAGCCGGGCCTTAGGGATAGCGTATAACGGGGGCCATGTCTCCGGACCGCACAACGGCCGCGCCGTCAAAGGTGCACACCCGAACCACGGGAGCCAGGGCCAAGGTGTCTCCTAGTTGGCCCGCGTGGGTCAGCCAGGCGACGAGCGCCTCGTAGAGCGGCAGCCTTCGCTCTCCATCCTGCATCAGGGCCGGGGCTTCGGGGTGAATGAGCTGGGCGGCCTCCCGCGTGACACTCTGCATCTGCAGGAGAGCGTTCACGTACCCGTCCTGGGCACTTAGCGCAAAGAGCCGGGGGATTAGCGTAAGGATGATGGTGGTTCCCTCCGTGATCGAGTAAACCATGTTAAGGACCAGCGATCGCAGCTCGGCGTTTACGGGGCCGAGTTGTTGGACGTCCGCCAGCAGCGAGAGGCGACTCCCGTTGTAGTACAGCACGTTGAGGTCTGGCAGCCCTCCGGGGTTTCTGGGGCTGGGGTTCAGGTCCCGGATGCCCCTGGCCACGAGCCGCGCCACGATTTCGCGCGCCAGGGGCGATGGAAGCGGAACGGGAAACCGCAACGTGAGGTCCAGCGAATCCAGGCGCACGTCCGTCGCTTGGCCCTCGAACACGGGCGGGACGAGGCTGATGGGGTCCCCGTTACAGAGATCTACGGGGGAGGTGTTGCGAAGGTTAACGGTGCCGGCGTGGGTGAGGCCCACGTCCAGGGGGCAGGCGACGATTCGCGTGGGAAGCACCCGGGTGATGACCGCGGGGAAGCGCCTTCGGTACGCCAGCAACAGCCCCAACGTGTCGGGACTGACGCCTCCGGAGACGAAGGATTCGTGCGCCACGTCGGCCAGCGTCAGTTGCCGGCGGATGGTCGGCAGGAATACCACCCGCCCTTCGCAGCGCTGCAGCGCCGCCGCATCGGGGCGCGAGATGCCCGAGGGTATCGCGATGTCAGTTTCAAAGCCGTCCGCCAGCATGGCGCCGATCCACGCGGCAGGGAGTGCAGTGGTGGTTCGGGTGGCGGGAGGAGCGCGGTGGGGGTCAGCGGCGTAGCAGAGACGGGCGACCAACCTCGCATAGGACGGGGGGTGGGTCTTAGGGGGTTGGGAGGCGACAGGGACCCCAGAGCATGCGCGGGGAGGTCTGTCGGGCCCAGACGCACCGAGAGCGAATCCGTCCATGGAGTCCCGGCCTGGGTTTTATGGGGCCCGGCCCTCGGAATCGCGGCTTGTCGGCGGGGACAAAGGGGGCGGGGCTAGGGGGCTTGCGGAAACAGAAGACGTGTGGGATAAAAGAATCGCACTACCCCAAGGAAGGGCGGGGCGGTTTATTACAGAGCCAGTCCCTTGAGCGGGGATGCGTCATAGACGAGATACTGCGCGAAGTGGGTCTCCCGCGCGTGGGCTTCCCCGTTGCGGGCGCTGCGGAGGAGGGCGGGGTCGCTGGCGCAGGTGAGCGGGTAGGCCTCCTGAAACAGGCCACACGGGTCCTCCACGAGTTCGCGGCACCCCGGGGGGCGCTTAAACTGTACGTCGCTGGCGGCGGTGGCCGTGGACACCGCCGAACCCGTCTCCACGATCAGGCGCTCCAGGCAGCGATGTTTGGCGGCGATGTCGGCCGACGTAAAGAACTTAAAGCAGGGGCTGAGCACCGGCGAGGCCCCGTTGAGGTGGTAGGCCCCGTTATAGAGCAGGTCCCCGTACGAAAATCGCTGCGACGCCCACGGGTTGGCCGTGGCCGCGAAGGCCCGGGACGGGTCGCTCTGGCCGTGGTCGTACATGAGGGCGGTGACATCCCCCTCCTTGTCCCCCGCGTAAACGCCCCCGGCGGCGCGTCCCCGGGGGTTGCAGGGCCGGCGGAAGTAGTTGACGTCGGTCGACACGGGGGTGGCGATAACTCACACACGGCGTCCTGGCCGTGGTCCATCCCTGCGCGCCGCGGCACCTGGGCGCCCCCGAACACGGGGACGGGCTGGGCCGGCCCCAGGCGGTTTCCCGCCACGACCGCGTTCCGCAGGTACACGGCTGCCGCGTTGTCCAGTAGAGGGGGAGCCCCGCGGCCCAGGTAAAAGTTTTGGGGAAGGTTGCCCATGTCGGTGACGGGGTTGCGGACGGTTGCCGTGGCCACGACGGCGGTGTAGCCCACGCCCAGGTCCACGTTCCCGCGCGGCTGGGTGAGCGTGAAGTTTACCCCCCCGCCAGTTTCATGCCGGGCCACCTGGAGCTGGCCCAGGAAGTACGCCTCCGACGCGCGCTCCGAGAACAGCACGTTCTCAGTCACAAAGCGGTCCTGTCGGACGACGGTGAACCCAAACCCGGGATGGAGGCCCGTCTTGAGCTGATGATGCAAGGCCACGGGACTGATCTTGAAGTACCCCGCCATGAGCGCGTAGGTCAGCGCGTTCTCCCCGGCCGCGCTCTCGCGGACGTGCTGCACGACGGGCTGTCGGATCGACGAAAAGTAGTTGGCCCCCAGAGCCGGGGGGACCAGGGGGACCTGCCGCGACAGGTCGCGCAGGGCCGGGGGGAAATTGGGCGCGTTCGCCACGTGGTCGGCCCCGGCGAACAGCGCGTGGACGGGGAGGGGGTAAAAATAGTCGCCATTTTGGATGGTATGGTCCAGATGCTGGGGGGCCATCAGCAGGATTCCGGCGTGCAACGCCCCGTCGAATATGCGCATGTTGGTGGTGGACGCGGTGTTGGCGCCCGCGTCGGGCGCCGCCGAGCAGAGCAGCGCCGTTGTGCGTTCGGCCATGTTGTGGGCCAGCACCTGCAGCGTGAGCATGGCGGGCCCGTCCACTACCACGCGCCCGTTGTGAAACATGGCGTTGACCGTGTTGGCCACCAGATTGGCCGGGGCAGGGGGTGCGCGGGGCCGTCACGGGGCGCTGGGGCAATCCTCGCCGGGGGTGATCTCCGGGACCACCATGTTCTGCAGGGTGGCGTATACGCGGTCGAAGCGAACCCCCGCGGTGCAGCAGCGGCCCCGCGAGAAGGCGGGCACCATCACGTAGTAGTAAATCTTGTGGTGCACGGTCCAGTCCGCCCCCCGGTGCGGCCGGTCGTCCGCGGCGTCCGCGGCTCGGGCCTGGGTGTTGTGCAGCAGCTGGCCGTCGTTGCGGTTGAAGTCCGCGGTCGCCACGTTACACGCCGCTGCGTACACGGGGTCGTGGCCCCCCGCGCTAACCCGGCAGTCGCGATGGCGGTCCAGGGCCGCGCGCCGCATCAGGGCGTCGCAGTCCCACACGAGGGGTGGCAGCAGCGCCGGGTCTCGCATTAGGTGATTCAGTTCGGCTTGCGCCTGCCCGCCCAGTTCCGGGCCGGTCAGGGTAAAGTCATCAACCAGCTGGGCCAGGGCCTCGACGTGCGCCACCAGGTCCCGGTACACGGCCATGCACTCCTCGGGAAGGTCTCCCCCGAGGTAGGTCACGACGTACGAGACCAGCGAGTAGTCGTTCACGAACGCCGCGCACCGCGTGTTGTTCCAGTAGCTGGTGATGCACTGGACCACGAGCCGGGCCAGGGCGCAGAAGACGTGCTCGCTGCCGTGTATGGCGGCCTGCAGCAGGTAAAACACCGCCGGGTAGTTGCGGTCTTCGAACGCCCCGCGAACGGCGGCGATGGTGGCGGGGGCTGGCGTGGCGTCCCACCCCCAGCTCCAGGCCCCGGGCGTCCCGGAACGCCGCCGGACATAGCGCCAGGGGCAAGTTGCCGTTCACCACGCGCCAGGTGGCCTGGATCTCCCCCGGGCCGGCCGGGGGAACGTCCCCCCCCGGCAGCTCCACGTCGGCCACCCCCACGAAGAAGTCGAACGCGGGGTGCAGCTCAAGAGCCAGGTTGGCGTTGTCGGGCTGCATAAACTGCTCCGGGGTCATCTGGCCTTCCGCGACCCATCGGACCCGCCCGTGGGCCAGGCGCTGCCCCCAGGCGTTCAAAAACAGCTGCTGCATGTCTGCGGCGGGGCCGGCCGGGGCCGCCACGTACGCCCCGTACGGATTGGCGGCTTCGACGGGGTCGCGGTTAAGGCCCCCGACCGCCGCGTCAACGTTCATCAGCGAAGGGTGGCACACGGTCCCGATCGCGTGTTCCAGAGACAGGCGCAGCACCTGGCGGTCCTTCCCCCAAAAAAACAGCTGGCGGGGCGGGAAGGCGCGGGGATCCGGGTGGCCGGGGGCGGGGCTAGGTCCCCGGCGTGCGCGGCAAACCGTTCCATGACCGGATTGAACAGGCCCAGGGGCAGGACGAACGTCAGGTCCATGGCGCCCACCAGGGGGTAGGGAACGTTGGTGGCGGCGTAGATGCGCTTCTCCAGGGCCTCCAAAAAGATCAGCTTCTCGCCGATGGACACCAGATCCGCGCGCACGCGCGTCGTCTGGGGGGCGCTCTCGAGCTCGTCCAGCGTCTGCCGGTTCAGGTCGAGCTGCTCCTCCTGCATCTCCAGCAGGTGGCGGCCCACGTCGTCCAGACTTCGCACGGCCTTGCCCATCACGAGCGCCGTGACCAGGTTGGCCCCGTTCAGGACCATCTCGCCGTACGTCACCGGCACGTCGGCTTCGGTGTCCTCCACTTTCAGGAAGGACTGCAGGAGGCGCTGTTTGATCGGGGCGGTGGTGACGAGCACCCCGTCGACCGGACGCCCGCGCGTGTCGGCATGCGTCAGACGGGGCACGGCCACGGAGGGCTGCGTGGCCGTGGTGAGGTCCACGAGCCAGGCCTCGACGGCCTCCCGGCGGTGGCCCGCCTTGCCCAGGAAAAAGCTCGTCTCGCAGAAGCTTCGCTTTAGCTCGGCGACCAGGGTCGCCCGGGCCACCCTGGTGGCCAGGCGGCCGTTGTCCAGGTATCGTTGCATCGGCAACAACAAAGCCAGGGGCGGCGCCTTTTCCAGCAGCACGTGCAGCATCTGGTCGGCCGTGCCGCGCTCAAACGCCCCGAGGACGGCCTGGACGTTGCGAGCGAGCTGTTGGATGGCGCGCAACTGGCGATGCGCGCTGATACCCGTCCCGTCCAGGGCCTCCCCCGTGAGCAGGGCGATGGCCTCGGTGGCCAGGCTGAAGGCGGCGTTCAGGGCCCGGCGGTCGATAATCTTGGTCATGTAATTGTGTGTGGGTTGCTCGATGGGGTGCGGGCCGTCGCGGGCAATCAGCGGCTGGTGGACCTCGAACTGTACGCGCCCCTCGTTCATGTAGGCCAGCTCCGGAAACTTGGTACACACGCACGCCACCGACAACCCGAGCTCCAGAAAGCGCACGAGCGACAGGGTGTTGCAATACGACCCCAACAGGGCGTCGAACTCGACGTCATACAGGCTGTTTGCATCGGAGCGCACGCGGGAAAAAAAATCGAACAGGCGTCGATGCGACGCCACCTCGATCGTGCTAAGGAGGGACCCGGTCGGCACCATGGCCGCGGCATACCGGTATCCCGGAGGGTCGCGGTTGGGAGCGGCCATGGGGTCGCGTGGAGATCGGCTGTCTCTAGCGATATTGGCCCGGGGAGGCTAAGATCCACCCCAACGCCCGGCCACCCGTGTACGTGCCCGACGGCCCAAGGTCCACCGAAAGACACGACGGGCCCGGACCCAAAAAGGCGGGGGATGCTGTGTGAGAGGCCGGGTGTCGGTCGGGGGGGAAAGGCACCGGGAGAAGGCTGCGGCCTCGTTCCAGGAGAACCCAGTGTCCCCAACAGACCCGGGGACGTGGGATCCAAGCTTGATCTCTATCACTGATAGGGAGATCTCTATCACTGATAGGGATCCCAGGCCTTATATACCCCCCCCGCCCCCCCCCGTTAGAACGCGACGGGTGCATTCAAGATGGCCCTGGTCCAAAAGCGTGCCAGGAAGAAATTGGCAGAGGCGGCAAAGCTGICCGCCGCCGCCACCCACATCGAGGCCCCGGCCGCGCAGGCTATCCCCAGGGCCCGTGTGCGCAGGGGATCGGTGGGCGGCAGCATTTGGTTGGTGGCGATAAAGTGGAAAAGCCCGTCCGGACTGAAGGTCTCGTGGGCGGCGGCGAACAAGGCACACAGGGCCGTGCCTCCCAAAAACACGGACATCCCCCAAAACACGGGCGCCGACAACGGCAGACGATCCCTCTTGATGTTAACGTACAGGAGGAGCGCCCGCACCGCCCACGTAACGTAGTAGCCGACGATGGCGGCCAGGATACAGGCCGGCGCCACCACCCTTCCGGTCAGCCCGTAATACATGCCCGCTGCCACCATCTCCAACGGCTTCAGGACCAAAAACGACCAAAGGAACAGAATCACGCGCTTTGAAAAGACCGGCTGGGTATGGGGCGGAAGACGCGAGTATGCCGAACTGACAAAAAAGTCAGAGGTGCCGTACGAGGACAATGAAAACTGTTCCTCCAGTGGCAGTTCTCCCTCCTCCCCCCCAAAGGCGGCCTCGTCGACCAGATCTCGATCCACCAGAGGAAGGTCATCCCGCATGGTCATGGGGTGTGCGGTGGAGGTGGGGAGACCGAAACCGCAAAGGGTCGCTTACGTCAGCAGGATCCCGAGATCAAAGACACCCGGGTTCTTGCACAAACACCACCCGGGTTGCATCCGCGGAGGCGAGTGTTTTGATAAGGCCGTTCCGCGCCTTGATATAACCTTTGATGTTGACCACAAAACCCGGAATTTACGCCTACGCCCCAATGCCCACGCAAGATGAGGTAGGTAACCCCCCCCCCGTGGGTGTGACGTTGCGTTTAGTTCATTGGAGGCCAAGGGGAAAATGGGGTGGGGAGGAAACGGAAAACCCAGTAGGCCGTGTTGGGAACACGCCCGGGGTTGTCCTCAAAAGGCAGGGTCCATACTACGGAAGCCGTCGTTGTATTCGAGACCTGCCTGTGCGACGCACGTCGGGGTTGCCTGTGTCCGGTTCGGCCCCACCGCGTGCGGCACGCACGAGGACGAGTCCGCGTGCTTTATTGGCGTTCCAAGCGTTGCCCTCCAGTTTCTGTTGTCGGTGTTCCCCCATACCCACGCCCACATCCACCGTAGGGGGCCTCTGGGCCGTGTCACGTCGCCGCCCGCGATGGAGCTTAGCTACGCCACCACCATGCACTACCGGGACGTTGTGTTTTACGTCACAACGGACCGAAACCGGGCCTACTTTGTGTGCGGGGGGTGTGTTTATTCCGTGGGGCGGCCGTGTGCCTCGCAGCCCGGGGAGATTGCCAAGTTTGGTCTGGTCGTTCGAGGGACAGGCCCAGACGACCGCGTGGTCGCCAACTATGTACGAAGCGAGCTCCGACAACGCGGCCTGCAGGACGTGCGTCCCATTGGGGAGGACGAGGTGTTTCTGGACAGCGTGTGTCTTCTAAACCCGAACGTGAGCTCCGAGCTGGATGTGATTAACACGAACGACGTGGAAGTGCTGGACGAATGTCTGGCCGAGTACTGCACCTCGCTGCGAACCAGCCCGGGTGTGCTAATATCCGGGCTGCGCGTGCGGGCGCAGGACAGAATCATCGAGTTGTTTGAACACCCAACGATAGTCAACGTTTCCTCGCACTTTGTGTATACCCCGTCCCCATACGTGTTCGCCCTGGCCCAGGCGCACCTCCCCCGGCTCCCGAGCTCGCTGGAGGCCCTGGTGAGCGGCCTGTTTGACGGCATCCCCGCCCCACGCCAGCCACTTGACGCCCACAACCCGCGCACGGATGTGGTTATCACGGGCCGCCGCGCCCCACGACCCATCGCCGGGTCGGGGGCGGGGTCGGGGGGCGCGGGCGCCAAGCGGGCCACCGTCAGCGAGTTCGTGCAAGTCAAACACATTGACCGCGTGGGCCCCGCTGGCGTTTCGCCGGCGCCTCCGCCAAACAACACCGACTCAAGTTCCCTGGTGCCCGGGGCCCAGGATTCCGCCCCGCCCGGCCCCACGCTAAGGGAGCTGTGGTGGGTGTTTTATGCCACAGACCGGGCGCTGGAGGAGCCCCGCGCCGACTCTGGCCTCACCCGCGAGGAGGTACGTGCCGTACGTGGGTTCCGGGAGCAGGCGTGGAAACTGTTTGGCTCCGCGGGGGCCCCGCGGGCGTTTATCGGGGCCGCGTTGGGCCTGAGCCCCCTCCAAAAGCTAGCCGTTTACTACTATATCATCCACCGAGAGAGGCGCCTGTCCCCCTTCCCCGCGCTAGTCCGGCTCGTAGGCCGGTACACACAGCGCCACGGCCTGTACGTCCCTCGGCCCGACGACCCAGTCTTGGCCGATGCCATCAACGGGCTGTTTCGCGACGCGCTGGCGGCCGGAACCACAGCCGAGCAGCTCCTCATGTTCGACCTTCTCCCCCCAAAGGACGTGCCGGTGGGAAGCGACGTGCAGGCCGACAGCACCGCTCTGCTGCGCTTTATAGAATCGCAACGTCTCGCCGTCCCCGGGGGGGTGATCTCCCCCGAGCACGTCGCGTACCTTGGTGCGTTCCTGAGCGTGCTGTACGCTGGCCGCGGGCGCATGTCCGCAGCCACGCACACCGCGCGGCTGACAGGGGTGACCTCCCTGGTGCTAGCGGTGGGTGACGTGGACCGTCTTTCCGCGTTTGACCGCGGAGCGGCGGGCGCGGCCAGCCGCACGCGGGCCGCCGGGTACCTGGATGTGCTTCTTACCGTTCGTCTCGCTCGCTCCCAACACGGACAGTCTGTGTAACAGACCCCAATAAACGTATGTCGCTACCACACCCTTGTGTGTCAATGGACGCCTCTCCGGGGGGGAAGGGAAAACAAAGAGGGGCTGGGGGAGCGGCACCACCGGGGCCTGAACAAACAAACCACAGACACGGTTACAGTTTATTCGGTCGGGCGGAGAAACGGCCGAAGCCACGCCCCCTTTATTCGCGTCTCCAAAAAAACGGGACACTTGTCCGGAGAACCTTTAGGATGCCAGCCAGGGCGGCGGTAATCATAACCACGCCCAGCGCAGAGGCGGCCAGAAACCCGGGCGCAATTGCGGCCACGGGCTGCGTGTCAAAGGCTAGCAAATGAATGACGGTTCCGTTTGGAAATAGCAACAAGGCCGTGGACGGCACGTCGCTCGAAAACACGCTTGGGGCGCCCTCCGTCGGCCCGGCGGCGATTTGCTGCTGTGTGTTGTCCGTATCCACCAGCAACACAGACATGACCTCCCCGGCCGGGGTGTAGCGCATAAACACGGCCCCCACGAGCCCCAGGTCGCGCTGGTTTTGGGTGCGCACCAGCCGCTTGGACTCGATATCCCGGGTGGAGCCTTCGCATGTCGCGGTGAGGTAGGTTAGGAACAGTGGGCGTCGGACGTCGACGCCGGTGAGCTTGTAGCCGATCCCCCGGGGCAGAGGGGAGTGGGTGACGACGTAGCTGGCGTTGTGGGTGATGGGTACCAGGATCCGTGGCTCGACGTTGGCAGACTGCCCCCCGCACCGATGTGAGGCCTCAGGGACGAAGGCGCGGATCAGGGCGTTGTAGTGTGCCCAGCGCGTCAGGGTCGAGGCGAGGCCGTGGGTCTGCTGGGCCAGGACTTCGACCGGGGTCTCGGATCGGGTGGCTTGAGCCAGCGCGTCCAGGATAAACACGCTCTCGTCTAGATCAAAGCGCAGGGAGGCCGCGCATGGCGAAAAGTGGTCCGGAAGCCAAAAGAGGGTTTTCTGGTGGTCGGCCCGGGCCAGCGCGGTCCGGAGGTCGGCGTTGGTCGCTGCGGCGACGTCGGACGTACACAGGGCCGAGGCTATCAGAAGGCTCCGGCGGGCGCGTTCCCGCTGCACCGCCGAGGGGACGCCCGCCAAGAACGGCTGCCGGAGGACAGCCGAGGCGTAAAATAGCGCCCGGTGGACGACCGGGGTGGTCAGCACGCGGCCCCCTAGAAACTCGGCATACAGGGCGTCGATGAGATGGGCTGCGCTGGGCGCCACTGCGTCGTACGCCGAGGGGCTATCCAGCACGAAGGCCAGCTGATAGCCCAGCGCGTGTAATGCCAAGCTCTGTTCGCGCTCCAGAATCTCGGCCACCAGGTGCTGGAGCCGAGCCTCTAGCTGCAGGCGGGCCGTGGGATCCAAGACTGACACATTAAAAAACACAGAATCCGCGGCACAGCCCGCGGCCCCGCGGGCGGCCAACCCGGCAAGCGCGCGCGAGTGGGCCAAAAAGCCTAGCAGGTCGGAGAGGCAGACCGCGCCGTTTGCGTGGGCGGCGTTCACGAAAGCAAAACCCGACGTCGCGAGCAGCCCCGTTAGGCGCCAGAAGAGAGGGGGACGCGGGCCCTGCTCGGCGCCCGCGTCCCCCGAGAAAAACTCCGCGTATGCCCGCGACAGGAACTGGGCGTAGTTCGTGCCCTCCTCCGGGTAGCCGCCCACGCGGCGGAGGGCGTCCAGCGCGGAGCCGTTGTCGGCCCGCGTCAGGGACCCTAGGACAAAGACCCGATACCGGGGGCCGCCCGGGGGCCCGGGAAGAGCCCCCGGGGGGTTTTCGTCCGCGGGGTCCCCGACCCGATCTAGCGTCTGGCCCGCGGGGACCACCATCACTTCCACCGGAGGGCTGICGTGCATGGATATCACGAGCCCCATGAATTCCCGCCCGTAGCGCGCGCGCACCAGCGCGGCATCGCACCCGAGCACCAGCTCCCCCGTCGTCCAGATGCCCACGGGCCACGTCGAGGCCGACGGGGAGAAATACACGTACCTACCTGGGGATCTCAACAGGCCCCGGGTGGCCAACCAGGTCGTGGACGCGTTGTGCAGGTGCGTGATGTCCAGCTCCGTCGTCGGGTGCCGCCGGGCCCCAACCGGCGGTCGGGGGGGCGGTGTATCACGCGGCCCGCTCGGGTGGCTCGCCGTCGCCACGTTGTCTCCCCGCGGGAACGTCAGGGCCTCGGGGTCAGGGACGGCCGAAAACGTTACCCAGGCCCGGGAACGCAGCAACACGGAGGCGGTTGGATTGTGCAAGAGACCCTTAAGGGGGGCGACCGCGGGGGGAGGCTGGGCGGTCGGCTCGACCGTGATGGGGGCGGGCAGGCTCGCGTTCGGGGGCCGGCCGAGCAGGTAGGTCTTCGAGATGTAAAGCAGCTGGCCGGGGTCCCGCGGAAACTCGGCCGTGGTGACCAATACAAAACAAAAGCGCTCCTCGTACCAGCGAAGAAGGGGCAGAGATGCCGTAGTCAGGTTTAGTTCGTCCGGCGGCGCCAGAAATCCGCGCGGTGGTTTTTGGGGGTCGGGGGTGTTTGGCAGCCACAGACGCCCGGTGTTCGTGTCGCGCCAGTACATGCGGTCCATGCCCAGGCCATCCAAAAACCATGGGTCTGTCTGCTCAGTCCAGTCGTGGACCTGACCCCACGCAACGCCCAAAAGAATAACCCCCACGAACCATAAACCATTCCCCATGGGGGACCCCGTCCCTAACCCACGGGGCCCGTGGCTATGGCAGGGCTTGCCGCCCCGACGTTGGCTGCGAGCCCTGGGCCTTCACCCGAACTTGGGGGTTGGGGTGGGGAAAAGGAAGAAACGCGGGCGTATTGGCCCCAATGGGGTCTCGGTGGGGTATCGACAGAGTGCCAGCCCTGGGACCGAACCCCGCGTTTATGAACAAACGACCCAACACCCGTGCGTTTTATTCTGTCTTTTTATTTCCGTCATAGCGCGGGTTCCTTCCGGTATTGTCTCCTTCCGTGTTTCAGTTAGCCTCCCCCATCTCCCGGGCAAACGTGCGCGCCAGGTCGCAGATCGTCGGTATGGAGCCTGGGGTGGTGACGTGGGTCTGGACCATCCCGGAGGTAAGTTGCAGCAGGGCGTCCCGGCAGCCGGCGGGCGATTGGTCGTAATCCAGGATAAAGACGTGCATGGGACGGAGGCGTTTGGCCAAGACGTCCAAGGCCCAGGCAAACACGTTATACAGGTCGCCGTTGGGGGCCAGCAACTCGGGGGCCCGAAACAGGGTAAATAACGTGTCCCCGATATGGGGTCGTGGGCCCGCGTTGCTCTGGGGCTCGGCACCCTGGGGCGGCACGGCCGTCCCCGAAAGCTGTCCCCAATCCTCCCGCCACGACCCGCCGCCCTGCAGATACCGCACCGTATTGGCAAGCAGCCCGTAAACGCGGCGAATCGCGGCCAACATAGCCAGGTCAAGCCGCTCGCCGGGGCGCTGGCGTTTGGCCAGGCGGTCGATGTGTCTGTCCTCCGGAAGGGCCCCCAACACGATGTTTGTGCCGGGCAAGGTCGGCGGGATGAGGGCCACGAACACCAGCACGGCCTGGGGGGTCATGCTGCCCATAAGGTATCGCGCGGCCGGGTAGCACAGGAGGGCGGCGATGGGATGGCGGTCGAAGATGAGGGTGAGGGCCGGGGGCGGGGCATGTGAGCTCCCAGCCTCCCCCCCGATATGAGGAGCCAGAACGGCGTCGGTCACGGCATAAGGCATGCCCATTGTTATCTGGGCGCTTGTCATTACCACCGCCGCGTCCCCGGCCGATATCTCACCCTGGTCGAGGCGGTGTTGTGTGGTGTAGATGTTCGCGATTGTCTCGGAAGCCCCCAGCACCTGCCAGTAAGTCATCGGCTCGGGTACGTAGACGATATCGTCGCGCGAACCCAGGGCCACCAGCAGTTGCGTGGTGGTGGTTTTCCCCATCCCGTGAGGACCGTCTATATAAACCCGCAGTAGCGTGGGCATTTTCTGCTCCAGGCGGACTTCCGTGGCTTCTTGCTGCCGGCGAGGGCGCAACGCCGTACGTCGGTTGCTATGGCCGCGAGAACGCGCAGCCTGGTCGAACGCAGACGCGTGTTGATGGCAGGGGTACGAAGCCATACGCGCTTCTACAAGGCGCTTGCCAAAGAGGTGCGGGAGTTTCACGCCACCAAGATCTGCGGCACGCTGTTGACGCTGTTAAGCGGGTCGCTGCAGGGTCGCTCGGTGTTCGAGGCCACACGCGTCACCTTAATATGCGAAGTGGACCTGGGACCGCGCCGCCCCGACTGCATCTGCGTGTTCGAATTCGCCAATGACAAGACGCTGGGCGGGGTTTGTGTCATCATAGAACTAAAGACATGCAAATATATTTCTTCCGGGGACACCGCCAGCAAACGCGAGCAACGGGCCACGGGGATGAAGCAGCTGCGCCACTCCCTGAAGCTCCTGCAGTCCCTCGCGCCTCCGGGTGACAAGATAGTGTACCTGTGCCCCGTCCTGGTGTTTGTCGCCCAACGGACGCTCCGCGTCAGCCGCGTGACCCGGCTCGTCCCGCAGAAGGTCTCCGGTAATATCACCGCAGTCGTGCGGATGCTCCAGAGCCTGTCCACGTATACGGTCCCCATGGAGCCTAGGACCCAGCGAGCCCGTCGCCGCCGCGGCGGCGCTGCCCGGGGGTCTGCGAGCAGACCGAAAAGGTCACCCTCTGGGGCACGCGACCCGCCCGGGCCAGCGGCCCGCCAGGTACCACCCGCCGACCAAACCCCCGCCTCCACGGAGGGCGGGGGGGTGCTTAAGAGGATCGCGGCGCTCTTCTGCGTGCCCGTGGCCACCAAGACCAAACCCCGAGCTGCCTCCGAATGAGAGTGTTTCGTTCCTTCCCCCTCCCCCCGCGTCAGACAAACCCTAACCACCGCTTAAGCGGCCCCCGCGAGGTCCGAAGACTCATTTGGATCCGGCGGGAGCCACCTGACAACAGCCCCCGGGTTTCCCCACGCCAGACGCCGGTCCGCTGTGCCATCGCTCCCCTTCATCCCACCCCCATCTTGTCCCCAAATAAAACAAGGTCTGGTAGTTAGGACAACGACCGCAGTTCTCGTGTGTTATTGTCGCTCTCCGCCTCTCGCAGATGGACCCGTATTGCCCATTTGACGCTCTGGACGTCTGGGAACACAGGCGCTTCATAGTCGCCGATTCCCGAAACTTCATCACCCCCGAGTTCCCCCGGGACTTTTGGATGTCGCCCGTCTTTAACCTCCCCCGGGAGACGGCGGCGGAGCAGGTGGTCGTCCTGCAGGCCCAGCGCACAGCGGCTGCCGCTGCCCTGGAGAACGCCGCCATGCAGGCGGCCGAGCTCCCCGTCGATATCGAGCGCCGGTTACGCCCGATCGAACGGAACGTGCACGAGATCGCAGGCGCCCTGGAGGCGCTGGAGACGGCGGCGGCCGCCGCCGAAGAGGCGGATGCCGCGCGCGGGGATGAGCCGGCGGGTGGGGGCGACGGGGGGGCGCCCCCGGGTCTGGCCGTCGCGGAGATGGAGGTCCAGATCGTGCGCAACGACCCGCCGCTACGATACGACACCAACCTCCCCGTGGATCTGCTACATATGGTGTACGCGGGCCGCGGGGCGACCGGCTCGTCGGGGGTGGTGTTCGGGACCTGGTACCGCACTATCCAGGACCGCACCATCACGGACTTTCCCCTGACCACCCGCAGTGCCGACTTTCGGGACGGCCGGATGTCCAAGACCTTCATGACGGCGCTGGTCCTGTCCCTGCAGTCGTGCGGCCGGCTGTATGTGGGCCAGCGCCACTATTCCGCCTTCGAGTGCGCCGTGTTGTGTCTCTACCTGCTGTACCGAAACACGCACGGGGCCGCCGACGATAGCGACCGCGCTCCGGTCACGTTCGGGGATCTGCTGGGCCGGCTGCCCCGCTACCTGGCGTGCCTGGCCGCGGTGATCGGGACCGAGGGCGGCCGGCCACAGTACCGCTACCGCGACGACAAGCTCCCCAAGACGCAGTTCGCGGCCGGCGGGGGCCGCTACGAACACGGAGCGCTGGCGTCGCACATCGTGATCGCCACGCTGATGCACCACGGGGTGCTCCCGGCGGCCCCGGGGGACGTCCCCCGGGACGCGAGCACCCACGTTAACCCCGACGGCGTGGCGCACCACGACGACATAAACCGCGCCGCCGCCGCGTTCCTCAGCCGGGGCCACAACCTATTCCTGTGGGAGGACCAGACTCTGCTGCGGGCAACCGCGAACACCATAACGGCCCTGGGCGTTATCCAGCGGCTCCTCGCGAACGGCAACGTGTACGCGGACCGCCTCAACAACCGCCTGCAGCTGGGCATGCTGATCCCCGGAGCCGTCCCTTCGGAGGCCATCGCCCGTGGGGCCTCCGGGTCCGACTCGGGGGCCATCAAGAGCGGAGACAACAATCTGGAGGCGCTATGTGCCAATTACGTGCTTCCGCTGTACCGGGCCGACCCGGCGGTCGAGCTGACCCAGCTGTTTCCCGGCCTGGCCGCCCTGTGTCTTGACGCCCAGGCGGGGCGGCCGGTCGGGTCGACGCGGCGGGTGGTGGTATGTCATCGGGGGCCCGCCAGGCGGCGCTGGGCGCCTCACCGCCCTGGAACTCATCAACCGCACCCGCACAAACCCCACCCCCGTGGGGGAGGTTATCCACGCCCACGACGCCCTGGCGATCCAATACGAACAGGGGCTTGGCCTGCTGGCGCAGCAGGCACGCATTGGCTTGGGCTCCAACACCAAGCGTTTCTCCGCGTTCAACGTTAGCAGCGACTACGACATGTTGTACTTTTTATGTCTGGGGTTCATTCCACAGTACCTGTCGGCGGTTTAGTGGGTGGTGGGCGAGGGGGGAGGGGGCATTAGGGAGAAAGAACAAGAGCCTCCGTTGGGTTTTCTTTGTGCCTGTACTCAAAAGGTCATACCCCGTAAACGGCGGGCTCCAGTCCCGGCCCGGCGGTTGGCGTGAACGCAACGGCGGGAGCTGGGTTAGCGTTTAGTTTAGCATTCGCTCTCGCCTTTCCGCCCGCCCCCGACCGTTGAGCCTTTTTTTTTTTTTTTTTTTTTTCGTCCACCAAAGTCTCTGTGGGTGCGCGCATGGCAGCCGATGCCCCGGGAGACCGGATGGAGGAGCCCCTGCCAGACAGGGCCGTGCCCATTTACGTGGCTGGGTTTTTGGCCCTGTATGACAGCGGGGACTCGGGCGAGTTGGCATTGGATCCGGATACGGTGCGGGCGGCCCTGCCTCCGGATAACCCACTCCCGATTAACGTGGACCACCGCGCTGGCTGCGAGGTGGGGCGGGTGCTGGCCGTGGTCGACGACCCCCGCGGGCCGTTTTTTGTGGGGCTGATCGCCTGCGGCAACTGGAGCGCGTCCTCGAGACGGCCGCCAGCGCTGCGATTTTCGAGCGCCGCGGGCCGCCGCTCTCCCGGGAGGAGCGCCTGTTGTACCTGATCACCAACTACCTGCCCTCGGTCTCCCTGGCCACAAAACGCCTGGGGGGCGAGGCGCACCCCGATCGCACGCTGTTCGCGCACGTAGCGCTGTGCGCGATCGGGCGGCGCCTTGGCACTATCGTCACCTACGACACCGGTCTCGACGCCGCCATCGCGCCCTTTCGCCACCTGTCGCCGGCGTCTCGCGAGGGGGCGCGGCGACTGGCCGCCGAGGCCGAGCTCGCGCTATCCGGACGCACCTGGGCGCCCGGCGTGGAGGCGCTGCCCACCCGCTGCTTTCCACCGCCGTTAACAACATGATGCTGCGGGACCGCTGGAGCCTGGTGGCCGAGCGGCGGCGGCAGGCCGGGATCGCCGGACACACCTACCTCCAGGCGAGCGAAAAATTCAAAATGTGGGGGGCGGAGCCTGTTTCCGCGCCGGCGCGCGGGTATAAGAACGGGGCCCCGGAGTCCACGGACATACCGCCCGGCTCGATCGCTGCCGCGCCGCAGGGTGACCGGTGCCCAATCGTCCGTCAGCGCGGGGTCGCCTCGCCCCCGGTACTGCCCCCCATGAACCCCGTTCCAACATCGGGCACCCCGGCCCCCGCGCCGCCCGGCGACGGGAGCTACCTGTGGATCCCGGCCTCCCATTACAACCAGCTCGTCGCCGGCCACGCCGCGCCCCAACCCCAGCCGCATTCCGCGTTTGGTTTCCCGGCTGCGGCGGGGGCCGTGGCCTATGGGCCTCACGGCGCGGGTCTTTCCCAGCATTACCCTCCCCACGTCGCCCATCAGTATCCCGGGGTGCTGTTCTCGGGACCCAGCCCACTCGAGGCGCAGATAGCCGCGTTGGTGGGGGCCATAGCCGCGGACCGCCAGGCGGGCGGTCAGCCGGCCGCGGGAGACCCTGGGGTCCGGGGGTCGGGAAAGCGTCGCCGGTACGAGGCGGGGCCGTCGGAGTCCTACTGCGACCAGGACGAACCGGACGCGGACTACCCGTACTACCCCGGGGAGGCTCGAGGCGGGCCGCGCGGGGTCGACTCTCGGCGCGCGGCCCGCCAGTCTCCCGGGACCAACGAGACCATCACGGCGCTGATGGGGGCGGTGACGTCTCTGCAGCAGGAACTGGCGCACATGCGGGCTCGGACCAGCGCCCCCTATGGAATGTACACGCCGGTGGCGCACTATCGCCCTCAGGTGGGGGAGCCGGAACCAACAACGACCCACCCGGCCCTTTGTCCCCCGGAGGCCGTGTATCGCCCCCCACCACACAGCGCCCCCTACGGTCCTCCCCAGGGTCCGGCGTCCCATGCCCCCACTCCCCCGTATGCCCCAGCTGCCTGCCCGCCAGGCCCGCCACCGCCCCCATGTCCTTCCACCCAGACGCGCGCCCCTCTACCGACGGAGCCCGCGTTCCCCCCCGCCGCCACCGGATCCCAACCGGAGGCATCCAACGCGGAGGCCGGGGCCCTTGTCAACGCCAGCAGCGCAGCACACGTGGACGTTGACACGGCCCGCGCCGCCGATTTGTTCGTCTCTCAGATGATGGGGGCCCGCTGATTCGCCCCGGTCTTTGGTACCATGGGATGTCTTACTGTATATCTTTTTAAATAAACCAGGTAATACCAAATAAGACCCATTGGTGTATGTTCTTTTTTTTTTATTGGGAGGGGCGGGTAGGCGGGTAGCTTTACAATGCAAAAGCCTTTGACGTGGAGGAAGGCGTGGGGGGGAGGAAATCGGCACTGACCAAGGGGGTCCGTTTTGTCACGGGAAAGGAAGAGGAAAAGGCGCGGCACCCGGGGGAGTTATGTGTTCCTTTTTCTTTCTTCCCACACACACACAAAAGGCGTACCAAACAAAAAAACCAAAAGATGCGCATGCGGTTTAACACCCGTGGTTTTTATTTACAACAAACCCCCCGTCACAGGTCGTCCTCGTCGGCGTCACCGTCTTTGTTGGGAACTTGGGTGTAGTTGGTGTTGCGGCGCTTGCGCATGACCATGTCGGTGACCTTGGCGCTGAGCAGCGCGCTCGTGCCCTTCTTCTTGGCCTTGTGTTCCGTGCGCTCCATGGCCGACACCAGGGCCATGTACCGTATCATCTCCCTGGCCTCGGCTAGCTTGGCCTCGTCAAAGTCGCCGCCCTCCTCGCCCTCCCCGGACGCGTCCGGGTTGGTGGGGTTCTTGAGCTCCTTGGTGGTTAGAGGGTACAGGGCCTTCATGGGGTTGCTCTGCAGCCGCATGACGTAACGAAAGGCGAAGAAGGCCGCCGCCAGGCCGGCCAGGACCAACAGACCCACGGCCAGCGCCCCAAAGGGGTTGGACATGAAGGAGGACACGCCCGACACGGCCGATACCACGCCGCCCACGATGCCCATCACCACCTTGCCGACCGCGCGCCCCAGGTCGCCCATCCCCTCGAAGAACGCGCCCAGGCCCGCGAACATGGCGGCGTTGGCGTCGGCGTGGATGACCGTGTCGATGTCGGCGAAGCGCAGGTCGTGCAGCTGGTTGCGGCGCTGGACCTCCGTGTAGTCCAGCAGGCCGCTGTCCTTGATCTCGTGGCGGGTGTACACCTCCAGGGGGACAAACTCGTGATCCTCCAGCATGGTGATGTTGAGGTCGATGAAGGTGCTGACGGTGGTGATGTCGGCGCGGCTCAGCTGGTGGGAGTACGCGTACTCCTCGAAGTACACGTAGCCCCCACCGAAGGTGAAGTAGCGCCGGTGTCCCACGGTGCACGGCTCGATCGCATCGCGCGTCAGCCGCAGCTCGTTGTTCTCCCCCAGCTGCCCCTCGACCAACGGGCCCTGGTCTTCGTACCGAAAGCTGACCAGGGGGCGGCTGTAGCAGGCCCCGGGCCGCGAGCTGATGCGCATCGAGTTTTGGACGATCACGTTGTCCGCGGCGACCGGCACGCACGTGGAGACGGCCATCACGTCGCCGAGCATCCGCGCGCTCACCCGCCGGCCCACGGTGACCGAGGCGATGGCGTTGGGGTTCAGCTTGCGGGCCTCGTTCCACAGGGTCAGCTCGTGATTCTGTAGCTCGCACCACGCGATGGCAACGCGGCCCAACATATCGTTGACATGGCGCTGTATGTGGTTGTACGTAAACTGCAGCCGGGCGAACTCGATGGAGGAGGTGGTCTTGATGCGCTCCACGGACGCGTTGGCGCTGGCCCCGGGCGGCGGGGGCGTGGGGTTTGGGGGCTTGCGGCTCTGCTCTCGGAGGTGTTCCCGCACGTACAGCTCCGCGAGCGTGTTGCTGAGAAGGGGCTGGTACGCGATCAGAAAGCCCCCATTGGCCAGGTAGTACTGCGGCTGGCCCACCTTGATGTGCGTCGCGTTGTACCTGCGGGCGAAGATGCGGTCCATGGCGTCGCGGGCGTCCTTGCCGATGCAGTCCCCCAGGTCCACGCGCGAGAGCGGGTACTCGGTCAGGTTGGTGGTGAAGGTGGTGGATATGGCGTCGGAGGAGAATCGGAAGGAGCCGCCGTACTCGGAGCGCAGCATCTCGTCCACTTCCTGCCACTTGGTCATGGTGCAGACCGACGGGCGCTTTGGCACCCAGTCCCAGGCCACGGTGAACTTGGGGGTCGTGAGCAGGTTCCGGGTGGTCGGCGCCGTGGCCCGGGCCTTGGTGGTGAGGTCGCGCGCGTAGAAGCCGTCGACCTGCTTGAAGCGGTCGGCGGCGTAGCTGGTGTGTTCGGTGTGCGACCCCTCCCGGTAGCCGTAAAACGGGGACATGTACACAAAGTCGCCAGTCGCCAGCACAAACTCGTCGTACGGGTACACCGAGCGCGCGTCCACCTCCTCGACGATGCAGTTTACCGTCGTCCCGTACCGGTGGAACGCCTCCACCCGCGAGGGGTTGTACTTGAGGTCGGTGGTGTGCCAGCCCCGGCTCGTGCGGGTCGCGGCGTTGGCCGGTTTCAGCTCCATGTCGGTCTCGTGGTCGTCCCGGTGAAACGCGGTGGTCTCCAGGTTGTTGCGCACGTACTTGGCCGTGGACCGACAGACCCCCTTGGCGTTGATCTTGTCGATCACCTCCTCGAAGGGGACGGGGGCGCGGTCCTCAAAGATCCCCATAAACTGGGAGTAGCGGTGGCCGAACCACACCTGCGAAACGGTGACGTCTTTGTAGTACATGGTGGCCTTGAACTTGTACGGGGCGATGTTCTCCTTGAAGACCACCGCGATGCCCTCCGTGTAGTTCTGACCCTCGGGCCGGGTCGGGCAGCGGCGCGGCTGCTCGAACTGCACCACCGTGGCGCCCGTGGGGGGTGGGCACACGTAAAAGTTTGCATCGGTGTTCTCCGCCTTGATGTCCCGCAGGTGCTCGCGCAGGGTGGCGTGGCCCGCGGCGACGGTCGCGCCCCCTTGGCGTTGATCTTGTCGATCACCTCCTCGAAGGGGACGGGGGCGCGGTCCTCAAAGATCCCCATAAACTGGGAGTAGCGGTGGCCGAACCACACCTGCGAAACGGTGACGTCTTTGTAGTACATGGTGGCCTTGAACTTGTACGGGGCGATGTTCTCCTTGAAGACCACCGCGATGCCCTCCGTGTAGTTCTGACCCTCGGGCCGGGTCGGGCAGCGGCGCGGCTGCTCGAACTGCACCACCGTGGCGCCCGTGGGGGGTGGGCACACGTAAAAGTTTGCATCGGTGTTCTCCGCCTTGATGTCCCGCAGGTGCTCGCGCAGGGTGGCGTGGCCCGCGGCGACGGTCGCGTTGTCGCCGGCGGGGCGGGGGCGTTGGGTTTTCGGTTTTTGTTCTTCTTCGGTTTCGGGTCCCCCGTTGGGGCGGCGCCAAGGGCGGGCGGCGCCGGAGTGGCAGGGCCCCCGTTCGCCGCCTGGGTCGCGGCCGCGACCCCAGGCGTGCCGGGGGAACTCGGAGCCGCCGACGCCACCAGGACCCCCAGCGTCAACCCCAAGAGCGCCCATACGACGAACCACCGGCGCCCCCACGAGGGGGCGCCCTGGTGCATGGCGGGACTACGGGGGCCCGTCGTGCCCCCCGTCAGGTAGCCTGGGGGCGAGGTGCTGGAGGACCGAGTAGAGGATCGAGAAAACGTCGCGGTCGTAGACCACGACCGACCGGGGGCCGATACAGCCGTCGGGGGCGCTCTCGACGATGGCCACCAGCGGACAGTCGGAGTCGTACGTGAGATATACGCCGGGCGGGTAACGGTAACGACCTTCGGAGGTCGGGCGGCTGCAGTCCGGGCGGCGCAACTCGAGCTCCCCGCACCGGTAGACCGAGGCAAAGAGTGTGGTGGCGATAATCAGCTCGCGAATATATCGCCAGGCGGCGCGCTGAGTGGGCGTTATTCCGGAAATGCCGTCAAAACAGTAAAACCTCTGAAATTCGCTGACGGCCCAATCAGCACCCGAGCCCCCCGCCCCCATGATGAACCGGGCGAGCTCCTCCTTCAGGTGCGGCAGGAGCCCCACGTTCTCGACGCTGTAATACAGCGCGGTGTTGGGGGGCTGGGCGAAGCTGTGGGTGGAGTGATCAAAGAGGGGCCCGTTGACGAGCTCGAAGAAGCGATGGGTGATGCTGGGGAGCAGGGCCGGGTCCACCTGGTGTCGCAGGAGAGACGCTCGCATGAACCGGTGCGCGTCGAACACGCCCGGCGCCGAGCGGTTGTCGATGACCGTGCCCGCGCCCGCCGTCAGGGCGCAGAAGCGCGCGCGCGCCGCAAAGCCGTTGGCGACCGCGGCGAACGTCGCGGGCAGCACCTCGCCGTGGACGCTGACCCGCAGCATCTTCTCGAGCTCCCCGCGCTGCTCGCGGACGCAGCGCCCCAGGCTGGCCAACGACCGCTTCGTCAGGCGGTCCGCGTACAGCCGCCGTCGCTCCCGTACGTCCGCGGCCGCTTGCGTGGCGATGTCCCCCCACGTCTCGGGCCCCTGCCCCCCGGGCCCGCGGCGACGGTCTTCGTCCTCGCCCCCGCCCCCGGGAGCTCCCAACCCCCGTGCCCCTTCCTCTACGGCGACACGGTCCCCGTCGTCGTCGGGGCCCGCGCCGCCCTTGGGCGCGTCCGCCGCGCCCCCCGCCCCCATGCGCGCCAGCACGCGACGCAGCGCCTCCTCGTCGCACTGTTCGGGGCTGACGAGGCGCCGCAAGAGCGGCGTCGTCAGGTGGTGGTCGTAGCACGCGCGGATGAGCGCCTCGATCTGATCGTCGGGTGACGTGGCCTGACCGCCGATTATTAGGGCGTCCACCATATCCAGCGCCGCCAGGTGGCTCCCGAACGCGCGATCGAAATGCTCCGCCCGCCGCCCGAACAGCGCCAGTTCCACGGCCACCGCGGCGGTCTCCTGCTGCAACTCGCGCCGCGCCAGCGCGGTCAGGTTGCTGGCAAACGCGTCCATGGTGGTCTGGCCGGCGCGGTCGCCGGACGCGAGCCAGAATCGCAATTCGCTGATGGCGTACAGGCCGGGCGTGGTGGCCTGAAACACGTCGTGCGCCTCCAGCAGGGCGTCGGCCTCCTTGCGGACCGAGTCGTTCTCGGGCGACGGGTGGGGCTGCCCGTCGCCCCCCGCGGTCCGGGCCAGCGCATGGTCCAACACGGAGAGCGCCCGCGCGCGGTCGGCGTCCGACAGCCCGGCGGCGTGGGGCAGGTACCGCCGCAGCTCGTTGGCGTCCAGCCGCACCTGCGCCTGCTGGGTGACGTGGTTACAGATACGGTCCGCCAGGCGGCGGGCGATCGTCGCCCCCTGGTTCGCCGTCACACACAGTTCCTCGAAACAGACCGCGCAGGGGTGGGACGGGTCGCTAAGCTCCGGGGGGACGATAAGGCCCGACCCCACCGCCCCCACCATAAACTCCCGAACGCGCTCCAGCGCGGCGGTGGCGCCGCGCGAGGGGGTGATGAGGTGGCAGTAGTTTAGCTGCTTTAGAAAGTTCTCGACGTCGTGCAGGAAACACAGCTCCATATGGACGGTCCCGCCATACGTATCCAGCCTGACCCGTTGGTGATACGGACAGGGTCGGGCCAGGCCCATGGTCTCGGTGAAAAACGCCGCGACGTCTCCCGCGGTCGCGAACGTCTCCAGGCTGCCCAGGAGCCGCTCGCCCTCGCGCCACGCGTACTCTAGCAGCAACTCCAGGGTGACCGACAGCGGGGTGAGAAAGGCCCCGGCCTGGGCCTCCAGGCCCGGCCTCAGACGACGCCGCAGCGCCCGCACCTGAAGCGCGTTCAGCTTCAGTTGGGGGAGCTTCCCCCGTCCGATGTGGGGGTCGCACCGCCGGAGCAGCTCTATCTGAAACACATAGGTCTGCACCTGCCCGAGCAGGGCTAACAACTTTTGACGGGCCACGGTGGGCTCGGACACCGGGGCGGCCATCTCGCGGCGCCGATCTGTACCGCGGCCGGAGTATGCGGTGGACCGAGGCGGTCCGTACGCTACCCGGTGTCTGGCTGAGCCCCGGGGTCCCCCTCTTCGGGGCGGCCTCCCGCGGGCCCGCCGACCGGCAAGCCGGGAGTCGGCGGCGCGTGCGTTTCTGTTCTATTCCCAGACACCGCGGAGAGGAATCGCGGCCCGCCCAGAGATATAGACACGGAACACAAACAAGCACGGATGTCGTAGCAATAATTTATTTTACACACATCCCCGCCCCGCCCTAGGTTCCCCCACCCCCCAACCCCTCACAGCATATCCAACGTCAGGTCTCCCTTTTTGTCGGGGGGCCCCTCCCCAAACGGGTCATCCCCGTGGAACGCCCGTTTGCGGCCGGCAAATGCCGGTCCCGGGGCCCCCGGGCCGCCGAACGGCGTCGCGTTGTCGTCCTCGCAGCCAAAATCCCCAAAGTTAAACACCTCCCCGGCGTTGCCGAGTTGGCTGACTAGGGCCTCGGCCTCGTGCGCCACCTCCAGGGCCGCGTCCGTCGACCACTCGCCGTTGCCGCGCTCCAGGGCACGCGCGGTCAGCTCCATCATCTCCTCGCTTAGGTACTCGTCCTCCAGGAGCGCCAGCCAGTCCTCGATCTGCAGCTGCTGGGTGCGGGGCCCCAGGCTTTTCACGGTCGCCACGAACACGCTACTGGCGACGGCCGCCCCGCCCTCGGAGATAATGCCCCGGAGCTGCTCGCACAGCGAGCTTTCGTGCGCTCCGCCGCCGAGGTTCGAGGCCGCGCACACAAACCCGGCCCGGGGACAGGCCAGGACGAACTTGCGGGTGCGGTCAAAAATAAGGAGCGGGCACGCGTTTTTGCCGCCCATCAGGCTGGCCCAGTTCCCGGCCTGAAACACACGGTCGTTGCCGGCCATGCCGTAGTATTTGCTGATGCTCAACCCCAACACGACCATGGGGCGCGCCGCCATGACGGGCCGCAGCAGGTTGCAGCTGGCGAACATGGACGTCCACGCGCCCGGATGCGCGTCCACGGCGTCCATCAGCGCGCGGGCCCCGGCCTCCAGGCCCGCCCCGCCCTGCGCGGACCACGCGGCCGCCGCCTGCACGCTGGGGGGACGGCGGGACCCCGCGATGATGGCCGTGAGGGTGTTGATGAAGTATGTCGAGTGATCGCAGTACCGCAGAATCTGGTTTGCCATGTAGTACATCGCCAGCTCGCTCACGTTGTTGGGGGCCAGGTTAATAAAGTTTATCGCGCCGTAGTCCAGGGAAAACTTTTTAATGAACGCGATGGTCTCGATGTCCTCGCGCGACAGGAGCCGGGCGGGAAGCTGGTTGCGTTGGAGGGCCGTCCAGAACCACTGCGGGTTCGGCTGGTTGGACCCCGGGGGCTTGCCGTTGGGGAAGATGGCCGCGTGGAACTGCTTCAGCAGAAAGCCCAGCGGTCCGAGGAGGATGTCCACGCGCTTGTCGGGCTTCTGGTAGGCGCTCTGGAGGCTGGCGACCCGCGCCTTGGCGGCCTCGGACGCGTTGGCGCTCGCGCCCGCGAACAACACGCGGCTCTTGACGCGCAGCTCCTTGGGAAACCCCAGGGTCACGCGGGCAACGTCGCCCTCGAAGCTGCTCTCGGCGGGGGCCGTCTGGCCGGCCGTTAGGCTGGGGGCGCAGATAGCCGCCCCCTCCGAGAGCGCGACCGTCAGCGTTTTGGCCGACAGAAACCCGTTGTTAAACATGTCCATCACGCGCCGCCGCAGCACCGGTTGGAATTGATTGCGAAAGTTGCGCCCCTCGACCGACTGCCCGGCGAACACCCCGTGGCACTGGCTCAGGGCCAGGTCCTGATACACGGCGAGGTTGGATCGCCGCCCGAGAAGCTGAAGCAGGGGGCATGGCCCGCACGCGTACGGGTCCAGCGTCAGGGACATGGCGTGGTTGGCCTCGCCCAGACCGTCGCGAAACTTGAAGTTCCTCCCCTCCACCAGGTTGCGCATCAGCTGCTCCACCTCGCGGTCCACGACCTGCCTGACGTTGTTCACCACCGTATGCAGGGCCTCGCGGTTGGTGATGATGGTCTCCAGCCGCCCCATGGCCGTGGGGACCGCCTGGTCCACGTACTGCAGGGTCTCGAGTTCGGCCATGACGCGCTCGGTCGCCGCGCGGTACGTCTCCTGCATGATGGTCCGGGCGGTCTCGGATCCGTCCGCGCGCTTCAGGGCCGAGAAGGCGGCGTAGTTTCCCAGCACGTCGCAGTCGCTGTACATGCTGTTCATGGTCCCGAAGACGCCGATGGCTCCGCGGGCGGCGCTGGCGAACTTGGGATGGCGCGCCCGGAGGCGCATGAGCGTCGTGTGTACGCAGGCGTGGCGCGTGTCGAAGGTGCACAGGTTGCAGGGCACGTCGGTCTGGTTGGAGTCCGCGACGTATCGAAACACGTCCATCTCCTGGCGCCCGACGATCACGCCGCCGTCGCAGCGCTCCAGGTAAAACAGCATCTTGGCCAGCAGCGCCGGGGAAAACCCACACAGCATGGCCAGGTGCTCGCCGGCAAATTCCTGGGTTCCGCCGACGAGGGGCGCGGTGGGCCGACCCTCGAACCCGGGCACCACGTGTCCCTCGCGGTCCACCTGTGGGTTGGCCGCCACGTGGGTCCCGGGCACGAGGAAGAAGCGGTAAAAGGAGGGTTTGCTGTGGTCCTTTGGGTCCGCCGGACCGGCGTCGTCCACCTCGGTGAGATGGAGGGCCGAGTTGGTGCTAAATACCATGGCCCCCACGAGTCCCGCGGCGCGCGCCAGGTACGCCCCGACGGCGTTGGCGCGGGCCGCGGCCGTGTCCTGGCCCTCGCACAGCGGCCACGCGGAGATGTCGGTGGGCGGCTCGTCGAAGACGGCCATCGACACGATAGACTCGAGGGCCAGGGCGGCGTCTCCGGCCATGACGGAGGCCAGGCGCTGTTCGAACCCGCCCGCCGGGCCCTTGCCGCCGCCGTCGCGCCCACCCCGCGGGGTCTTACCCTGGCTGGCTTCGAAGGCCGTGAACGTAATGTCGGCGGGGAGGGCGGCGCCCTCGTGGTTTTCGTCAAACGCCAGGTGGGCGGCCGCGCGGGCCACGGCGTCCACGTTTCGGCATCGCAGTGCCACGGCGGCGGGTCCCACGACCGCCTCGAACAGGAGGCGGTTGAGGGGGCGGTTAAAAAACGGAAGCGGGTAGGTAAAATTCTCCCCGATCGATCGGTGGTTGGCGTTGAACGGCTCGGCGATGACCCGGCTAAAATCCGGCATGAACAGCTGCAACGGATACACGGGTATGCGGTGCACCTCCGCCCCGCCTATGGTTACCTTGTCCGAGCCTCCCAGGTGCAGAAAGGTGTTGTTGATGCACACGGCCTCCTTGAAGCCCTCGGTAACGACCAGATACAGGAGGGCGCGGTCCGGGTCCAGGCCGAGGCGCTCACACAGCGCCTCCCCCGTCGTCTCGTGTTTGAGGTCGCCGGGCCGGGGGGTGTAGTCCGAAAAGCCAAAATGGCGGCGTGCCCGCTCGCAGAGTCGCGTCAGGTTTGGGGCCTGGGTGCTGGGGTCCAGGTGCCGGCCGCCGTGAAAGACGTACACGGACGAGCTGTAGTGCGATGGCGTCAGTTTCAGGGACACCGCGGTACCCCCGAGCCCCGTCGTGCGAGAACCCACGACCACGGCTACGTTGGCCTCAAAGCCGCTCTCCACGGTCAGGCCCACGACCAGGGGCGCCACGGCGACGTCGGCATCGCCGCTGCGCGCCGACAGTAACGCCAGAAGCTCGATGCCTTCGGACGGACACGCGCGAGCGTACACGTATCCCAGGGGCCCGGGGGGGACCTTGATGGTGGTTGCCGTCTTGGGCTTTGTCTCCATGTCCTCCTGGCAATCGGTCCGCAAACGGAGGTAATCCCGGCACGACGACGGACGCCCGACGAGGTATGTCTCCCGAGCGTCAAAATCCGGGGGGGGGGGGGGGGGGGGGGCGGCGACGGTCAAGGGGAGGGTGGGAGACCGGGGTTGGGGAATGAATCCCTACCCTTCACAGACAACCCCCGGGTAACCACGGGGTGCCGATGAACCCCGGCGGCTGGCAACGCGGGGTCCCTGCGAGAGGCACAGATGCTTACGGTCAGGTGCTCCGGGCCGGGTGCGTCTGATATGCGGTTGGTATATGTACACTTTACCTGGGGGCGTGCCGGACCGCCCCAGCCCCTCCCACACCCCGCGCGTCATCAGCCGGTGGGCGTGGCCGCTATTATAAAAAAAGTGAGAACGCGAAGCGTTCGCACTTTGTCCTAATAATATATATATTATTAGGACAAAGTGCGAACGCTTCGCGTTCTCACTTTTTTTATAATAGCGGCCACGCCCACCGGCTACGTCACGCTCCTGTCGGCCGCCGGCGGTCCATAAGCCCGGCCGGCCGGGCCGACGCGAATAAACCGGGCCGCCGGCCGGGGCGCCGCGCAGCAGCTCGCCGCCCGGATCCGCCAGACAAACAAGGCCCTTGCACATGCCGGCCCGGGCGAGCCTGGGGGTCCGGTAATTTTGCCATCCCACCCAAGCGGCTTTTGGGGTTTTTCCTCTTCCCCCCTCCCCACATCCCCCCTCTTTAGGGGTTCGGGTGGGAACAACCGCGATGTTTTCCGGTGGCGGCGGCCCGCTGTCCCCCGGAGGAAAGTCGGCGGCCAGGGCGGCGTCCGGGTTTTTTGCGCCCGCCGGCCCTCGCGGAGCCGGCCGGGGACCCCCGCCTTGTTTGAGGCAAAACTTTTACAACCCCTACCTCGCCCCAGTCGGGACGCAACAGAAGCCGACCGGGCCAACCCAGCGCCATACGTACTATAGCGAATGCGATGAATTTCGATTCATCGCCCCGCGGGTGCTGGACGAGGATGCCCCCCCGGAGAAGCGCGCCGGGGTGCACGACGGTCACCTCAAGCGCGCCCCCAAGGTGTACTGCGGGGGGGACGAGCGCGACGTCCTCCGCGTCGGGTCGGGCGGCTTCTGGCCGCGGCGCTCGCGCCTGTGGGGCGGCGTGGACCACGCCCCGGCGGGGTTCAACCCCACCGTCACCGTCTTTCACGTGTACGACATCCTGGAGAACGTGGAGCACGCGTACGGCATGCGCGCGGCCCAGTTCCACGCGCGGTTTATGGACGCCATCACACCGACGGGGACCGTCATCACGCTCCTGGGCCTGACTCCGGAAGGCCACCGGGTGGCCGTTCACGTTTACGGCACGCGGCAGTACTTTTACATGAACAAGGAGGAGGTTGACAGGCACCTACAATGCCGCGCCCCACGAGATCTCTGCGAGCGCATGGCCGCGGCCCTGCGCGAGTCCCCGGGCGCGTCGTTCCGCGGCATCTCCGCGGACCACTTCGAGGCGGAGGTGGTGGAGCGCACCGACGTGTACTACTACGAGACGCGCCCCGCTCTGTTTTACCGCGTCTACGTCCGAAGCGGGCGCGTGCTGTCGTACCTGTGCGACAACTTCTGCCCGGCCATCAAGAAGTACGAGGGTGGGGTCGACGCCACCACCCGGTTCATCCTGGACAACCCCGGGTTCGTCACCTTCGGCTGGTACCGTCTCAAACCGGGCCGGAACAACACGCTAGCCCAGCCGCGGGCCCCGATGGCCTTCGGGACATCCAGCGACGTCGAGTTTAACTGTACGGCGGACAACCTGGCCATCGAGGGGGGCATGAGCGACCTACCGGCATACAAGCTCATGTGCTTCGATATCGAATGCAAGGCGGGGGGGGAGGACGAGCTGGCCTTTCCGGTGGCCGGGCACCCGGAGGACCTGGTTATTCAGATATCCTGTCTGCTCTACGACCTGTCCACCACCGCCCTGGAGCACGTCCTCCTGTTTTCGCTCGGTTCCTGCGACCTCCCCGAATCCCACCTGAACGAGCTGGCGGCCAGGGGCCTGCCCACGCCCGTGGTTCTGGAATTCGACAGCGAATTCGAGATGCTGTTGGCCTTCATGACCCTTGTGAAACAGTACGGCCCCGAGTTCGTGACCGGGTACAACATCATCAACTTCGACTGGCCCTTCTTGCTGGCCAAGCTGACGGACATTTACAAGGTCCCCCTGGACGGGTACGGCCGCATGAACGGCCGGGGCATGTTTCGCGTGTGGGACATAGGCCAGAGCCACTTCCAGAAGCGCAGCAAGATAAAGGTGAACGGCATGGTGAACATCGACATGTACGGGATCATAACCGACAAGATCAAGCTCTCGAGCTACAAGCTCAACGCCGTGGCCGAAGCCGTCCTGAAGGACAAGAAGAAGGACCTGAGCTATCGCGACATCCCCGCCTACTACGCCACCGGGCCCGCGCAACGCGGGGTGATCGGCGAGTACTGCATACAGGATTCCCTGCTGGTGGGCCAGCTGTTTTTTAAGTTTTTGCCCCATCTGGAGCTCTCGGCCGTCGCGCGCTTGGCGGGTATTAACATCACCCGCACCATCTACGACGGCCAGCAGATCCGCGTCTTTACGTGCCTGCTGCGCCTGGCCGACCAGAAGGGCTTTATTCTGCCGGACACCCAGGGGCGATTTAGGGGCGCCGGGGGGGAGGCGCCCAAGCGTCCGGCCGCAGCCCGGGAGGACGAGGAGCGGCCAGAGGAGGAGGGGGAGGACGAGGACGAACGCGAGGAGGGCGGGGGCGAGCGGGAGCCGGAGGGCGCGCGGGAGACCGCCGGCCGGCACGTGGGGTACCAGGGGGCCAGGGTCCTTGACCCCACTTCCGGGTTTCACGTGAACCCCGTGGTGGTGTTCGACTTTGCCAGCCTGTACCCCAGCATCATCCAGGCCCACAACCTGTGCTTCAGCACGCTCTCCCTGAGGGCCGACGCAGTGGCGCACCTGGAGGCGGGCAAGGACTACCTGGAGATCGAGGTGGGGGGGCGACGGCTGTTCTTCGTCAAGGCTCACGTGCGAGAGAGCCTCCTCAGCATCCTCCTGCGGGACTGGCTCGCCATGCGAAAGCAGATCCGCTCGCGGATTCCCCAGAGCAGCCCCGAGGAGGCCGTGCTCCTGGACAAGCAGCAGGCCGCCATCAAGGTCGTGTGTAACTCGGTGTACGGGTTCACGGGAGTGCAGCACGGACTCCTGCCGTGCCTGCACGTTGCCGCGACGGTGACGACCATCGGCCGCGAGATGCTGCTCGCGACCCGCGAGTACGTCCACGCGCGCTGGGCGGCCTTCGAACAGCTCCTGGCCGATTTCCCGGAGGCGGCCGACATGCGCGCCCCCGGGCCCTATTCCATGCGCATCATCTACGGGGACACGGACTCCATATTTGTGCTGTGCCGCGGCCTCACGGCCGCCGGGCTGACGGCCATGGGCGACAAGATGGCGAGCCACATCTCGCGCGCGCTGTTTCTGCCCCCCATCAAACTCGAGTGCGAAAAGACGTTCACCAAGCTGCTGCTGATCGCCAAGAAAAAGTACATCGGCGTCATCTACGGGGGTAAGATGCTCATCAAGGGCGTGGATCTGGTGCGCAAAAACAACTGCGCGTTTATCAACCGCACCTCCAGGGCCCTGGTCGACCTGCTGTTTTACGACGATACCGTATCCGGAGCGGCCGCCGCGTTAGCCGAGCGCCCCGCAGAGGAGTGGCTGGCGCGACCCCTGCCCGAGGGACTGCAGGCGTTCGGGGCCGTCCTCGTAGACGCCCATCGGCGCATCACCGACCCGGAGAGGGACATCCAGGACTTTGTCCTCACCGCCGAACTGAGCAGACACCCGCGCGCGTACACCAACAAGCGCCTGGCCCACCTGACGGTGTATTACAAGCTCATGGCCCGCCGCGCGCAGGTCCCGTCCATCAAGGACCGGATCCCGTACGTGATCGTGGCCCAGACCCGCGAGGTAGAGGAGACGGTCGCGCGGCTGGCCGCCCTCCGCGAGCTAGACGCCGCCGCCCCAGGGGACGAGCCCGCCCCCCCCGCGGCCCTGCCCTCCCCGACCAAGCGCCCCCGGGAGACGCCGTCGCATGCCGACCCCCCGGGAGGCGCGTCCAAGCCCCGCAAGCTGCTGGTGTCCGAGCTGGCCGAGGATCCCGCATACGCCATTGCCCACGGCGTCGCCCTGAACACGGACTATTACTTCTCCCACCTGTTGGGGGCGGCGTGCGTGACATTCAAGGCCCTGTTTGGGAATAACGCCAAGATCACCGAGAGTCTGTTAAAAAGGTTTATTCCCGAAGTGTGGCACCCCCCGGACGACGTGGCCGCGCGGCTCCGGGCCGCAGGGTTCGGGGCGGTGGGTGCCGGCGCTACGGCGGAGGAAACTCGTCGAATGTTGCATAGAGCCTTTGATACTCTAGCATGAGCCCCCCGTCGAAGCTGATGTCCCTCATTTTACAATAAATGTCTGCGGCCGACACGGTCGGAATCTCCGCGTCCGTGGGTTTCTCTGCGTTGCGCCGGACCACGAGCACAAACGTGCTCTGCCACACGTGGGCGACGAACCGGTACCCCGGGCACGCGGTGAGCATCCGGTCTATGAGCCGGTAGTGCAGGTGGGCGGACGTGCCGGGAAAGATGACGTACAGCATGTGGCCCCCGTAAGTGGGGTCCGGGTAAAACAACAGCCGCGGGTCGCACGCCCCGCCTCCGCGCAGGATCGTGTGGACGAAAAAAAGCTCGGGTTGGCCAAGAATCCCGGCCAAGAGGTCCTGGAGGGGGGCGTTGTGGCGGTCGGCCAACACGACCAAGGAGGCCAGGAAGGCGCGATGCTCGAATATCGTGTTGATCTGCTGCACGAAGGCCAGGATTAGGGCCTCGCGGCTGGTGGCGGCGAACCGCCCGTCTCCCGCGTTGCACGCGGGACAGCAACCCCCGATGCCTAGGTAGTAGCCCATCCCGGAGAGGGTCAGGCAGTTGTCGGCCACGGTCTGGTCCAGACAGAAGGGCAGCGACACGGGAGTGGTCTTCACCAGGGGCACCGAGAACGAGCGCACGATGGCGATCTCCTCGGAGGGCGTCTGGGCGAGGGCGGCGAAAAGGCCCCGATAGCGCTGGCGCTCGTGTAAACACAGCTCCTGTTTGCGGGCGTGAGGCGGCAGGCTCTTCCGGGAGGCCCGACGCACCACGCCCAGAGTCCCGCCGGCCGCAGAGGAGCACGACCGCCGGCGCTCCTTGCCGTGATAGGGCCCGGGCCGGGAGCCGCGGCGATGGGGGTCGGTATCATACATAGGTACACAGGGTGTGCTCCAGGGACAGGAGCGAGATCGAGTGGCGTCTAAGCAGCGCGCCCGCCTCACGGACAAATGTGGCGAGCGCGGTGGGCTTTGGTACAAATACCTGATACGTCTTGAAGGTGTAGATGAGGGCACGCAACGCTATGCAGACACGCCCCTCGAACTCGTTCCCGCAGGCCAGCTTGGCCTTGTGGAGCAGCAGCTCGTCGGGATGGGTGGCGGGGGGATGGCCGAACAGAACCCAGGGGTCAACCTCCATCTCCGTGATGGCGCACATGGGGTCACAGAACATGTGCTTAAAGATGGCCTCGGGCCCCGCGGCCCGCAGCAGGCTCACAAACCGGCCCCCGTCCCCGGGCTGCGTCTCGGGGTCCGCCTCGAGCTGGTCGACGACGGGTACGATACAGTCGAAGAGGCTCGTGTTGTTTTCCGAGTAGCGGACCACGGAGGCCCGGAGTCTGCGCAGGGCCAGCCAGTAAGCCCGCACCAGTAACAGGTTACACAGCAGGCATTCTCCGCCGGTGCGCCCGCGCCCCCGGCCGTGTTTCAGCACGGTGGCCATCAGAGGGCCCAGGTCGAGGTCGGGCTGGGCATCGGGTTCGGTAAACTGCGCAAAGCGCGGAGCCACGTCGCGCGTGCGTGCCCCGCGATGCGCTTCCCAGGACTGGCGGACCGTGGCGCGACGGGCCTCCGCGGCAGCGCGCAGCTGGGGCCCCGACTCCCAGACGGCGGGGGTGCCGGCGAGGAGCAGCAGGACCAGATCCGCGTACGCCCACGTATCCGGCGACTCCTCCGGCTCGCGGTCCCCGGCGACCGTCTCGAATTCCCCGTTGCGAGCGGCGGCGCGCGTACAGCAGCTGTCCCCGCCCCCGCGCCGACCCTCCGTGCAGTCCAGGAGACGGGCGCAATCCTTCCAGTTCATCAGCGCGGTGGTGAGCGACGGCTGCGTGCCGGATCCCGCCGCCGACCCCGCCCCCTCCTCGCCCCCGGAGGCCAAGGTTCCGATGAGGGCCCGGGTGGCAGACTGCGCCAGGAACGAGTAGTTGGAGTACTGCACCTTGGCGGCTCCCGGGGAGGGCGAGGGCTTGGGTTGCTTCTGGGCATGCCGCCCGGGCACCCCGCCGTCGGTACGGAAGCAGCAGTGGAGAAAAAAGTGCCGGTGGATGTCGTTTATGGTGAGGGCAAAGCGTGCGAAGGAGCCGACCAGGGTCGCCTTCTTGGTGCGCAGAAAGTGGCGGTCCATGACGTACACAAACTCGAACGCGGCCACGAAGATGCTAGCGGCGCAGTGGGGCGCCCCCAGGCATTTGGCACAGAGAAACGCGTAATCGGCCACCCACTGGGGCGAGAGGCGGTAGGTTTGCTTGTACAGCTCGATGGTGCGGCAGACCAGACAGGGCCGGTCCAGCGCGAAGGTGTCGATGGCCGCCGCGGAAAAGGGCCCGGTGTCCAAAAGCCCCTCCCCACAGGGATCCGGGGGCGGGTTGCGGGGTCCTCCGCGCCCGCCCGAACCCCCTCCGTCGCCCGCCCCCCCGCGGGCCCTTGAGGGGGCGGTGACCACGTCGGCGGCGACGTCCTCGTCGAGCGTACCGACGGGCGGCACACCTATCACGTGACTGGCCGCCAGGAGCTCGGCGCAGAGAGCCTCGTTAAGAGCCAGGAGGCTGGGATCGAAGGCCACATACGCGCGCTCGAACGCCCCCGCCTTCCAGCTGCTGCCGGGGGACTCTTCGCACACCGCGACGCTCGCCAGGACCCCGGGGGGCGAAGTTGCCATGGCTGGGCGGGAGGGGCGCACGCGCCAGCGAACTTTACGGGACACAATCCCCGACTGCGCGCTGCGGTCCCAGACCCTGGAGAGTCTAGACGCGCGCTACGTCTCGCGAGACGGCGCGCATGACGCGGCCGTCTGGTTCGAGGATATGACCCCCGCCGAGCTGGAGGTTGTCTTCCCGACTACGGACGCCAAGCTGAACTACCTGTCGCGGACGCAGCGGCTGGCCTCCCTCCTGACGTACGCCGGGCCTATAAAAGCGCCCGACGACGCCGCCGCCCCGCAGACCCCGGACACCGCGTGTGTGCACGGCGAGCTGCTCGCCCGCAAGCGGGAAAGATTCGCGGCGGTCATTAACCGGTTCCTGGACCTGCACCAGATTCTGCGGGGCTGACGCGCGCGCTGTTGGGCGGGACGGTTCGCGAACCCTTTGGTGGGTTTACGCGGGCACGCACGCTCCCATCGCGGGCGCCATGGCGGGACTGGGCAAGCCCTACCCCGGCCACCCAGGTGACGCCTTCGAGGGTCTCGTTCAGCGAATTCGGCTTATCGTCCCATCTACGTTGCGGGGCGGGGACGGGGAGGCGGGCCCCTACTCTCCCTCCAGCCTCCCCTCCAGGTGCGCCTTTCAGTTTCATGGCCATGACGGGTCCGACGAGTCGTTTCCCATCGAGTATGTACTGCGGCTTATGAACGACTGGGCCGAGGTCCCGTGCAACCCTTACCTGCGCATACAGAACACCGGCGTGTCGGTGCTGTTTCAGGGGTTTTTTCATCGCCCACACAACGCCCCCGGGGGCGCGATTACGCCAGAGCGGACCAATGTGATCCTGGGCTCCACCGAGACGACGGGGCTGTCCCTCGGCGACCTGGACACCATCAAGGGGCGGCTCGGCCTGGATGCCCGGCCGATGATGGCCAGCATGTGGATCAGCTGCTTTGTGCGCATGCCCCGCGTGCAGCTCGCGTTTCGGTTCATGGGCCCCGAAGATGCCGGACGGACGAGACGGATCCTGTGCCGCGCCGCCGAGCAGGCTATTACCCGTCGCCGCCGAACCCGGCGGTCCCGGGAGGCGTACGGGGCCGAGGCCGGGCTGGGGGTGGCTGGAACGGGTTTCCGGGCCAGGGGGGACGGTTTTGGCCCGCTCCCCTTGTTAACCCAAGGGCCCTCCCGCCCGTGGCACCAGGCCCTGCGGGGTCTTAAGCACCTACGGATTGGCCCCCCCGCGCTCGTTTTGGCGGCGGGACTCGTCCTGGGGGCCGCTATTTGGTGGGTGGTTGGTGCTGGCGCGCGCCTATAAAAAAGGACGCACCGCCGCCCTAATCGCCAGTGCGTTCCGGACGCCTTCGCCCCACACAGCCCTCCCGTCCGACACCCCCATATCGCTTCCCGACCTCCGGTCCCGATGGCCGTCCCGCAATTTCACCGCCCCAGCACCGTTACCACCGATAGCGTCCGGGCGCTTGGCATGCGCGGGCTCGTCTTGGCCACCAATAACTCTCAGTTTATCATGGATAACAACCACCCGCACCCCCAGGGCACCCAAGGGGCCGTGCGGGAGTTTCTCCGCGGTCAGGCGGCGGCGCTGACGGACCTTGGTCTGGCCCACGCAAACAACACGTTTACCCCGCAGCCTATGTTCGCGGGCGACGCCCCGGCCGCCTGGTTGCGGCCCGCGTTTGGCCTGCGGCGCACCTATTCACCGTTTGTCGTTCGAGAACCTTCGACGCCCGGGACCCCGTGAGGCCCGGGGAGTTCCTTCTGGGGTGTTTTAATCAATAAAAGACCACACCAACGCACGAGCCTTGCGTTTAATGTCGTGTTTATTCAAGGGAGTGGGATAGGGTTCGACGGTTCGAAACTTAACACACAAAATAATCGAGCGCGTCTAGCCCAGTAACATGCGCACGTGATGTAGGCTGGTCAGCACGGCGTCGCTGTGATGAAGCAGCGCCCGGCGGGTCCGCTGTAACTGCTGTTGTAGGCGGTAACAGGCGCGGATCAGCACCGCCAGGGCGCTACGACCGGTGCGTTGCACGTAGCGTCGCGACAGAACTGCGTTTGCCGATACGGGCGGGGGGCCGAATTGTAAGCGCGTCACCTCTTGGGAGTCATCGGCGGATAACGCACTGAATGGTTCGTTGGTTATGGGGGAGTGTGGTTCCCGAGGGAGTGGGTCGAGCGCCTCGGCCTCGGAATCCGAGAGGAACAACGAGGTGGTGTCGGAGTCTTCGTCGTCAGAGACATACAGGGTCTGAAGCAGCGACACGGGCGGGGGGGTAGCGTCAATGTGTAGCGCGAGGGAGGATGCCCACGAAGACACCCCAGACAAGGAGCTGCCCGTGCGTGGATTTGTGGACGACGCGGAAGCCGGGACGGATGGGCGGTTTTGCGGTGCCCGGAACCGAACCGCCGGATACTCCCCGGGTGCTACATGCCCGTTTTGGGGCTGGGGTTGGGGCTGGGGCTGGGGCGGGGGGTGGGGGGGGTTGGGGTGGGGCTGGGGTGGGGCTGGGGTTGGGGCTGGGGCTGGGGCTGGGGCTGGGGTGGGGTTGGGGTTGGGGCTGGGGCTGGGGTGGGGTGGGGCTGGGGTGGGGTTGGGGCTGGGGTTGGGGCTGGGGTTGGGGCTGGGGTGGGGCTGGGGTTGGGGTTGGGGTTGGGGCTGGGGTTGGGGCTGGGGCGCGGACAGGCGGTTGACGGTCAAATGCCCCCGGGGGCGCGCAGATGTGGTGGGCGTGGCCACCGGCTGCCGGGTAGGGGGGCGGCGGGGAACCGGGCCTCCGGGCGTAACACCGCCCTCCAGCGTCAAGGATGTGGGGGGCGGGCCTGACGTCGGGGGCGGGGTGACGGGTTGGACCGCGGGAGGCGGGGGAGAGGGACCTGCGGGAGAGGATGAGGTCGGCTCGGCCGGGTTGCGGCCTAAAACAGGGGCCGTGGGGTCGGCGGGGTCCCAGGGTGAAGGGAGGGATTCCCGCGATTCGGACAGCGACGCGACAGCGGGGCGCGTAAGGCGCCGCTGCGGCCCGCCTACGGGAACCCTGGGGGGGGTTGGCGCGGGACCCGAGGTTAGCGGGGGGCGGCGGTTTTCGCCCCCGGGCAAAACCGTGCCGGTTGCGACCGGGGGCGGAACGGGATCGATAGGGAGAGCGGGAGAAGCCTGGCCGGCGAACTGGGGACCGAGCGGGAGGGGCACACCAGACACCAAAGCGTGGAGCGCTGGCTCTGGGGGTTTGGGAGGGGCCGGGGGGCGCGCGAAATCGGTAACCGGGGCGACCGTGTCGGGGAGGGCAGGCGGCCGCCAACCCTGGGTGGTCGCGGAAGCCTGGGTGGCGCGCGCCAGGGAGCGTGCCCGGCGGTGTCGGCGCGCGCGCGACCCGGACGAAGAAGCGGCAGAAGCGCGGGAGGAGGCGGGGGGGCGGGGGGCGGTGGCATCGGGGGGCGCCGGGGAACTTTGGGGGGACGGCAAGCGCCGGAAGTCGTCGCGGGGGCCCACGGGCGCCGGCCGCGTGCTTTCGGCCGGGACGCCCGGTCGTGCTTCGCGAGCCGTGACTGCCGGCCCAGGGGGCCGCGGTGCACACTGGGACGTGGGGACGGACTGATCGGCGGTGGGCGAAAGGGGGTCCGGGGCAAGGAGGGGCGCGGGGCCGCCGGAGTCGTCAGACGCGAGCTCCTCCAGGCCGTGAATCCATGCCCACATGCGAGGGGGGACGGGCTCGCCGGGGGTGGCGTCGGTGAATAGCGTGGGGGCCAGGCTTCCGGGCCCCAACGAGCCCTCCGTCCCAACAAGGTCCGCCGGGCCGGGGGTCGGGTTCGGGACCGAGGGGCTCTGGTCGTCGGGGGCGCGCTGGTACACCGGATGCCCCGGGAATAGCTCCCCCGACAGGAGGGAGGCGTCGAACGGCCGCCCGAGGATAGCTCGCGCGAGGAAGGGGTCCTCGTCGGTGGCGCTGGCGGCGAGGACGTCCTCGCCGCCCGCCACAAACGGGAGCTCCTCGGTGGCCTCGCTGCCAACAAACCGCACGTCGGGGGGGCCGGGGGGGTCCGGGTTTTCCCACAACACCGCGACCGGGGTCATGGAGATGTCCACGAGCACCAGACACGGCGGGCCCCGGGCGAGGGGCCGCTCGGCGATGAGCGCGGACAGGCGCGGGAGCTGTGCCGCCAGACACGCGTTTTCAATCGGGTTCAGGTCGGCGTGCAGGAGGCGGACGGCCCACGTCTCGATGTCGGACGACACGGCATCGCGCAAGGCGGCGTCCGGCCCGCGAGCGCGTGAGTCAAACAGCGTGAGACACAGCTCCAGCTCCGACTCGCGGGAAAAGGCCGTGGTGTTGCGGAGCGCCACGACGACGGGCGCGCCCAGGAGCACTGCCGCCAGCACCAGGTCCATGGCCGTAACGCGCGCCGCGGGGGTGCGGTGGGTGGCGGCGGCCGGCACGGCGACGTGCTGGCCCGTGGGCCGGTAGAGGGCGTTGGGGGGAGCGGGGGGTGACGCCTCGCGCCCCCCCGAGGGGCTCAGCGTCTGCCCAGATTCCAGACGCGCGGTCAGAAGGGCGTCGAAACTGTCATACTCTGTGTAGTCGTCCGGAAACATGCAGGTCCAAAGAGCGGCCAGAGCGGTGCTTGGGAGACACATGCGCCCGAGGACGCTCACCGCCGCCAGCGCCTGGGCGGGACTCAGCTTTCCCAGCGCGGCGCCGCGCTCGGTTCCCAGCTCGGGGACCGAGCGCCAGGGCGCCAGGGGGTCGGTTTCGGACAACTTGCCGCGGCGCCAGTCTGCCAGCCGCGTGCCGAACATGAGGCCCCGGGTCGGAGGGCCTCCGGTCGAAAACACTGGCAGCACGCGGATGCGGGCGTCTGGATGCGGGGTCAGGCGCTGCACGAATAGCATGGAATCTGCTGCGTTCTGAAACGCACGGGGGAGGGTGAGATGCATGTACTCGTGTTGGCGGACCAGATCCAGGCGCCAAAAGGTGTAAATGTGTTCCGGGGAGCTGGCCACCAGCGCCACCAGCACGTCGTTCTCGTTAAAGGAAACGCGGTGCCTAGTGGAGCTGTGGGGCCCGAGCGGCGGTCCCGGGGCCGCCGCGTCACCCCCCCATTCCAGCTGGGCCCAGCGACACCCAAACTCGCGCGTGAGAGTGGTCGCGACGAGGGCGACGTAGAGCTCGGCCGCCGCATCCATCGAGGCCCCCCATCTCGCCTGGCGGTGGCGCACAAAGCGTCCGAAGAGCTGAAAGTTGGCGGCCTGGGCGTCGCTGAGGGCCAGCTGAAGCCGGTTGATGACGGTGATGACGTACATGGCCGTGACGGTCGAGGCCGACTCCAGGGTGTCCGTCGGAAGCGGGGGGCGAATGCATGCCGCCTCGGGACACATCAGCAGCGCGCCGAGCTTGTCGGTCACGGCCGGGAAGCAGAGCGCGTACTGCAGTGGCGTTCCATCCGGGACCAAAAAGCTGGGGGCGAACGGCCGATCCAGCGTACTGGTGGCCTCGCGCAGCACCAGGGGCCCCGGGCCTCCGCTCACTCGCAGGTACGCCTCGCCCCGGCGGCGCAGCATCTGCGGGTCGGCCTCTTGGCCGGGTGGGGCGGACGCCCGGGCGCGGGCGTCTAGGGCGCGAAGATCCACGAGCAGGGGCGCGGGCGCGGCGGCCGCGCCCGCGCCCGTCTGGCCTGTGGCCTTGGCGTACGCGCTATATAAGCCCATGCGGCGTTGGATGAGCTCCCGCGCGCCCCGGAACTCCTCCACCGCCCATGGGGCCAGGTCCCCGGCCACCGCGTCGAATTCCGCCAACAGGCCCCCCAGGGTGTCAAAGTTCATCTCCCAGGCCACCCTTGGCACCACCTCGTCCCGCAGCCGGGCGCTCAGGTCGGCGTGTTGGGCCACGCGCCCCCCGAGCTCCTCCACGGCCCCGGCCCGCTCGGCGCTCTTGGCGCCCAGGACGCCCTGGTACTTGGCGGGAAGGCGCTCGTAGTCCCGCTGGGCTCGCAGCCCCGACACAGTGTTGGTGGTGTCCTGCAGGGCGCGAAGCTGCTCGCATGCCGCGCGAAATCCCTCGGGCGATTTCCAGGCCCCCCCGCGAACGCGGCCGAAGCGACCCCATACCTCGTCCCACTCCGCCTCGGCCTCCTCGAGAGACCTCCGCAGGGCCTCGACGCGGCGACGGGTGTCGAAGAGCGCCTGCAGGCGCGCGCCCTGTCGCGTCAGGAGGCCCGGGCCGTCGCCGCTGGCCGCGTTTAGCGGGTGCGTCTCAAAGGTACGCTGGGCATGTTCCAACCAGGCGACCGCCTGCACGTCGAGCTCGCGCGCCTTCTCCGTCTGGTCCAACAGAATTTCGACCTGATCCGCGATCTCCTCCGCCGAGCGCGCCTGGTCCAGCGTCTTGGCCACGGTCGCCGGGACGGCGACCACCTTCAGCAGGGTCTTCAGATTGGCCAGACCCTCGGCCTCGAGCTGGGCCCGGCGCTCGCGCGCGGCCAGCACCTCCCGCAGCCCCGCCGTGACCCGCTCGGTGGCTTCGGCGCGCTGCTGTTTGGCGCGCACCACGGCGTCCTTGGTATCGGCCAGGTCCTGTCGGGTCACGAATGCGACGTAGTCGGCGTACGCCGTGTCCTTCACGGGGCTCTGGTCCACGCGCTCCAGCGCCGCCACGCACGCCACCAGCGCGTCCTCGCTCGGGCAGGGCAGGGTGACCCCTGCCCGGACAAGCTCGGCGGCCGCCGCCGGGTCGTTGCGCACCGCGGATATCTCCTCCGCGGCGGCGGCCAGGTCCAGCGCCACGCTTCCGATCGCGCGCCGCGCGTCGGCCCGGAGGGCGTCCAGGCGATCGCGGATATCCACGTACTCGGCGTAGCCCTTTTGAAAAAACGGCACGTACTGGCGCAGGGCCGGCACGCCCCCCAAGTCTTCCGACAGGTGTAGGACGGCCTCGTGGTAGTCGATAAACCCGTCGTTCGCCTGGGCCCGCTCCAGCAGCCCCCCCGCCAGCCGCAGAAGCCGCGCCAGGGGCTCGGTGTCCACCCGAAACATGTCGGCGTACGTGTCGGCCGCGGCCCCGAAGGCCGCGCTCCAGTCGATGCGGTGAATGGCTGCGAGCGGGGGGAGCATGGGGTGGCGCTGGTTCTCGGGGGTGTATGGGTTAAACGCAAGGGCCGTCTCCAGGGCAAGGGTCACCGCCTTGGCGTTGGTTCCCAGCGCCTGTTCGGCCCGCTTTCGGAAGTCCCGGGGGTTGTAGCCGTGCGTGCCCGCCAGCGCCTGCAGGCGACGGAGCTCGACCACGTCAAACTCGGCACCGCTTTCCACGCGGTCCAGCACGGCCTCCACGTCGGCGGCCCAGCGCTCGTGGCTACTGCGGGCGCGCTGGGCCGCCATCTTCTCTCTCAGGTCGGCGATGGCGGCCTCAAGTTCGTCGGCGCGGCGTCGCGTGGCGCCGATGACCTTTCCCAGCTCCTGCAGGGCGCGCCCGCTGGGGGAGTGGTCCCCGGCCGTCCCTTCGGCGTGCAACAGGCCCCCGAACCTGCCCTCGTGGCCCGCGAGGCTTTCCCGCGCGCCGGTGGTCGCGCGCGTCGCGGCCTGGATCAGGGAGGCATGCTCTCCCTCCGGTTGGTTGGCGGCCCGGCGCACCTGGACGACAAGGTCGGCTGCCGCCGACCCTAAGGTCGTGAGCTGGGCGATGGCCCCCCGCGCGTCCAGGGCCAACCGAGTCGCCTTGACGTATCCCGCGGCGCTGTCGGCCATGGCCGCTAGGAAGGCCAGGGGGGAGGCCGGGTCGCTGGCGGCCGCGCCCAGGGCCGTCACCGCGTCGACCAGGACGCGGTGCGCCCGCACGGCCGCATCCACCGTCGACGCGGGGTCTGCCGTCGCGACGGCGGCGCTGCCGGCGTTGATGGCGTTCGAGACGGCGTGGGCTATGATCGGGGCGTGATCGGCGAAGAACTGCAAGAGAAACGGAGTCTCTGGGGCGTCGGCGAACAGGTTCTTCAGCACCACCACGAAGCTGGGATGCAAGCCAGACAGAGCCGTCGCCGTGTCCGGAGTCGGGTGCTCCAGGGCATCTCGGTACTGCCCCAGCAGCCCCCACATGTCCGCCCGCAGTGCCGCCGTAACCTCAGGGGGCGCCCCCCGAACGGCCTCGGGGAGGTCCGACCAGCCCGCCGGCAGGGAGGCCCGCAGGGTCGCCAGGACGGCCGGACAGGCCTTTAGCCCCACAAAGTCAGGGAGGGGGCGCAGGACCCCCTGGAGTTTGTGCAAGAACTTCTCCCGGGCGTCGCGGGCCACCTTCGCCCGCTCCCGCGCTCCCTCGAGCATTGCCTCCAGGGAGCGCGCGCGCTCCCGCAAACGGGCACGCGCATCGGGGGCGAGCTCTGCCGTCAGCTTGGCGGCATCCATGGCCCGCGCCTGCCGCAGCGCTTCCTCGGCCATGCGCGTGGCCTCTGGCGACAGCCCGCCGTCGTCGGGGTAGGGCGACGCGCCGGGCGCAGGAACAAAGGCCGCGTCGCTGTCCAGCTGCTGGCCCAGGGCCGCATCTAGGGCGTCGAAGCGCCGCAGCTCGGCCAGACCCGAGCTGCGGCGCGCCTGCTGGTCGTTAATGTCGCGGATGCTGCGCGCCAGCTCGTCCAGCGGCTTGCGTTCTATCAGCCCTTGGTTGGCGGCGTCCGTCAGGACGGAGAGCCAGGCCGCCAGGTCCTCGGGGGCGTCCAGCGTCTGGCCCCGCTGGATCAGATCCCGCAACAGGATGGCCGTGGGGCTGGTCGCGATCGGGGGCGGGGCGGGAATGGCGGCGCGCTGCGCGATGTCCCGCGTGTGCTGGTCGAAGACAGGCAGGGACTCGAGCAGCTGGACCACGGGCACGACGGCGGCCGAAGCCACGTGAAACCGGCGGTCGTTGTTGTCGCTGGCCTGTAGAGCCTTGGCGCTGTATACGGCCCCCCGGTAAAAGTACTCCTTAACCGCGCCCTCGATCGCCCGACGGGCCTGGGTCCGCACCTCCTCCAGCCGAACCTGAACGGCCTCGGGGCCCAGGGGGGGTGGGCGCGGAGCCCCCTGCGGGGCCGCCCCGGCCGGGGCGGGCATTACGCCGAGGGGCCCGGCGTGCTGTGAGACCGCGTCGACCCCGCGAGCGAGGGCGTCGAGGGCCTCGCGCATCTGGCGATCCTCCGCCTCCACCCTAATCTCTTCGCCACGGGCAAATTTGGCCAGAGCCTGGACTCTATACAGAAGCGGTTCTGGGTGCGTCGGGGTGGCGGGGGCAAAAAGGGTGTCCGGGTGGGCCTGCGAGCGCTCCAGAAGCCACTCGCCGAGGCGTGTATACAGATTGGCCGGCGGGGCCGCGCGAAGCTGCAGCTCCAGGTCCGCGAGTTCCCCGTAAAAGGCGTCCGTCTCCCGAATGACATCCCTAGCCACAAGGATCAGCTTCGCCAGCGCCAGGCGACCGATCAGAGAGTTTTCGTCCAGCACGTGCTGGACGAGGGGCAGATGGGCGGCCACGTCGGCCAGGCTCAGGCGCGTGGAGGCCAGAAAGTCCCCCACGGCCGTTTTCCGGGGCAGCATGCTCAGGGTAAACTCCAGCAGGGCGGCGGCCGGGCCGGCCACCCCGGCCTGGGTGTGCGTCCGGGCCCCGTTCTCGATGAGAAAGGCGAGGACGCGTTCAAAGAAAAAAATAACACAGAGCTCCAGCAGCCCCGGAGAAGCCGGATACGGCGACCGTAAGGCGCTGATGGTGAGCCGCGAACACGCGGCGCCCTCGCGGGCCAGGGTGGCGGAGCACGCGGTGAACTTAACCGCCGTGGCGGCCACGTTTGGGTGGGCCTCGAACAGCTGGGCGAGGTCTGCGCCCGGGGGCTCGGGTGAGCGGCGAGTCTTCAGCGCCTCGAGGGCCTGTGAGGACGCCGGAACCATGGGCCCGTCGTCCTCGCCCGCCTCGGCGACCGGCGGCCCGGCCGGGTCGGGGGGTGCCGAGGCGAGGACAGGCTCCGGAACGGAGGCGGGGACCGCGGCCCCGACGGGGGTTTGCCTTTGGGGGTGGGTTTCTTCTTGGTTTTGGCAGGGGGGGCCGAGCGTTTCGTTTTCTCCCCCGAAGTCAGGTCTTCGACGCTGGAAGGCGGAGTCCAGGTGGGTCGGCGGCGCTTGGGAAGGCCGGCCGAGTAGCGTGCCCGGTGCCGACCAACCGGGACGACGCCCATCTCCAGGACCCGCATGTCGTCGTCATCTTCTTCGGCCGCCTCTGCGGCGGGGGTCTTGGGGGCGGAGGGAGGCGGTGGTGGGATCGCGGAGGGTGGGTCGGCGGAGGGGGGATCCGTGGGTGGGGTACCCTTTAGGGCCACCGCCCATACATCGTCGGGCGCCCGATTCGGGCGCTTGGCCTCTGGTTTTGCCGACGGACCGGCCGTCCCCCGGGATGTCTCGGAGGCCCTGTCGTCGCGACGGGCCCGGGTCGGTGGCGGCGACTGGGCGGCTGTGGGCGGGTGTGGCCCCGGCCCCCCTCCCCCCTCCCGGGGGCCCACGCCGACGCAGGGCTCCCCCAGGCCCGCGATCTCGCCCCGCAGGGGGTGCGTGATGGCCACGCGCCGTTCGCTGAACGCTTCGTCCTGCATGTAAGTCTCGCTGGCCCCGTAAAGATGCAGAGCCGCGGCCGTCAAGTCCGCAGGAGCCGCGGGTTCCGGGCCCGACGGCACGAAAAACACCATGGCTCCCGCCCACCGTACGTCCGGGCGATCGCGGGTGTAATACGTCAGGTATGGATACATGTCCCCCGCCCGCACTTTGGCGATGAACGCGGGGGTGCCCTCCGGAAGGCCATGCGGGTCAAAAAGGTATGCGGTGTCGCCGTCCCTGAACAGCCCCATCCCTAGGGGGCCAATGGTTAGGAGCGTGTACGACAGGGGGCGCAGGGCCCACGGGCCGGCGAAGAACGTGTGTGCGGGGCATTGTGTCTCCAGCAGGCCTGCCGCGGGCTCCCCGAAGAAGCCCACCTCGCCGTATACGCGCGAGAAGACACAGCGCAGTCCGCCGCGCGCCCCTGGGTACTCGAGGAAGTTGGGGAGCTCGACGATCGAACACATGCGCGGCGGCCCAGGGCCCGCAGTCGCGCGCGTCCACTCGCCCCCCTCGACCAAACATCCCTCGATGGCCTCCGCGGACAGAACGTCGCGAGGGCCCACATCAAATATGAGGCTGAGAAAGGACAGCGACGAGCGCATGCACGATACCGACCCCCCCGGCTCCAGGTCGGGCGCGAACTGGTTCCGAGCACCGGTGACCACGATGTCGCGATCCCCCCCGCGTTCCATCGTGGAGTGCGGTGGGGTGCCCGCGATCATATGTGCCCTGCGGGCCAGAGACCCGGCCTGTTTATGGACCGGACCCCCGGGGTTAGTGTTGTTTCCGCCACCCACGCCCCCGTACCATGGCCCCGGTTCCCCTGATTAGGCTACGAGTCGCGGTGATCGCTTCCCAAAAACCGAGCTGCGTTTGTCTGTCTTGGTCTTCCCCCCCCCCAGCCCGCACACCATAACACCGAGAACAACACACGGGGGTGGGCGGAACATAATAAAGCTTTATTGGTAACTAGTTAACGGCAAGTCCGTGGGTGGCGCGACGGTGTCCTCCGGGATCATCTCGTCGTCCTCGACGGGGGTGTTGGAATGAGGCGCCTCCTCGCGGTCCACCTGGCGTGGGCCGTGCCCATAGGCCTCCGGCTTCTGTGCGTCCATGGGCGTAGGCGCGGGGAGACTGTTTCCGGCGTCGCGGACCTCCAGGTCCCTGGGAGCCTCCGGTCCGGCTAACGGACGAAACGCGGAAGCGCGAAACACGCCGTCGGTGACCCGCAGGAGCTCGTTCATCAGTAACCAATCCATACTCAGCGTAACGGCCAGCCCCTGGCGAGACAGATCCACGGAGTCCGGAACCGCGGTCGTCTGGCCCAGGGGGCCGAGGCTGTAGTCCCCCCAGGCCCCTAGGTCGCGACGGCTCGTAAGCACGACGCGGTCGGCCGCGGGGCTTTGCGGGGGGGCGTCCTCGGGCGCATGCGCCATTACCTCTCGGATGGCCGCGGCGCGCTGGTCGGCCGAGCTGACCAAGGGCGCCACGACCACGGCGCGCTCCGTCTGCAGGCCCTTCCACGTGTCGTGGAGTTCCTGGACAAACTCGGCCACGGGCTCGGGTCCCGCGGCCGCGCGCGCGGCTTGATAGCAGGCCGACAGACGCCGCCAGCGCGCTAGAAACTGACCCATGAAACAAAACCCGGGGACCTGGTCTCCCGACAGCAGCTTCGACGCCCGGGCGTGAATGCCGGACACGACGGACAGAAACCCGTGAATTTCGCGCCGGACCACGGCCAGCACGTTGTCCTCGTGCGACACCTGGGCTGCCAGCTCGTCGCACACCCCCAGGTGCGCCGTGGTTTCGGTGATGACGGAACGCAGGCTCGCGAGGGACGCGACCAGCGCGCGCTTGGCGTCGTGATACATGCTGCAGTACTGACTCACCGCGTCCCCCATGGCCTCGGGGGGCCAGGGCCCCAGGCGGTCGGGCGTGTCCCCGACCACCGCATACAGGCGGCGCCCGTCGCTCTCGAACCGACACTCGAAAAAGGCGGAGAGCGTGCGCATGTGCAGCCGCAGCAGCACGATGGCGTCCTCCAGTTGGCGAATCAGGGGGTCGGCGCGCTCGGCGAGGTCCTGCAGCACCCCCCGGGCAGCCAGGGCGTACATGCTAATCAACAGGAGGCTGGTGCCCACCTCGGGGGGCGGGGGGGGCTGCAGTTGGACCAGGGGCCGCAGCTGCTCGACGGCACCCCTGGAGATCACGTACAGCTCCCGGAGCAGCTGCTCTATGTTGTCGGCCATCTGCATAGTGGGGCCGAGGCCGCCCCGGGCGGCCGGTTCGAGGAGAGTGATCAGCGCGCCCAGTTTGGTGCGATGGCCCTCGACCGTGGGGAGATAGCCCAGCCCAAAGTCCCGGGCCCAGGCCAACACACGCAGGGCGAACTCGACCGGGCGGGGAAGGTAGGCCGCGCTACACGTGGCCCTCAGCGCGTCCCCAACCACCAGGGCCAGAACGTAGGGGACGAAGCCCGGGTCGGCGAGGACGTTGGGGTGAATGCCCTCGAGGGCGGGGAAGCGGATCTGGGTCGCCGCGGCCAGGTGGACAGAGGGGGCATGGCTGGGCTGCCCGACGGGGAGAAGCGCGGACAGCGGCGTGGCCGGGGTGGTGGGGGTGATGTCCCAGTGGGTCTGACCATACACGTCGATCCAGATGAGCGCCGTCTCGCGGAGAAGGCTGGGTTGACCGGAACTAAAGCGGCGCTCGGCCGTCTCAAACTCCCCCACGAGCGCCCGCCGCAGGCTCGCCAGATGTTCCGTCGGCACGGCCGGCCCCATGATACGCGCCAGCGTCTGGCTCAGAACGCCCCCCGACAGGCCGACCGCCTCACAGAGCCGCCCGTGCGTGTGCTCGCTGGCGCCCTGGACCCGCCTGAAAGTTTTTACGTAGTTGGCATAGTACCCGTATTCCCGCGCCAGACCAAACACGTTCGACCCCGCGAGGGCAATGCACCCAAAGAGCTGCTGGACTTCGCCGAGTCCGTGGCCGGCGGGCGTCCGCGCGGGGACGCCCGCCGCCAGAAACCCCTCCAGGGCCGAAAGGTAGTGCGTGCAGTGCGAGGGCGTGAACCCAGCGTCGATCAGGGTGTTGATCACCACGGAGGGCGAATTGGTATTCTGGATCAACGTCCACGTCTGCTGCAGCAGAGCCAGCAGCCGCTGCTGGGCGCCGGCGGAGGGCTGCTCCCCGAGCTGCAGCAGGCTGGAGACGGCAGGCTGGAAGACTGCCAGTGCCGACGAACTCAGGAACGGCACGTCGGGATCAAACACGGCCACGTCCGTCCGCACGCGCGCCATTAGCGTCCCCGGGGGCGCACAGGCCGAGCGCGGGCTGACGCGGCTGAGGGCCGTCGACACGCGCACCTCCTCGCGGCTGCGAACCATCTTGTTGGCCTCCAGTGGCGGAATCATTATGGCCGGGTCGATCTCCCGCACGGTGTGCTGAAACTGCGCCAACAGGGGCGGCGGGACCACAGCCCCCCGCTCGGGGGTCGTCAGGTACTCGTCCACCAGGGCCAACGTAAAGAGGGCCCGTGTGAGGGGAGTGAGGGTCGCGTCGTCTATGCGCTGGAGGTGCGCCGAGAACAGCGTCACCCGATTACTCACCAGGGCCAAGAACCGGAGGCCCTCTTGCACGAACGGGGCGGGGAAGAGCAGGCTGTACACCGGGGTGGTAAGGTTCGCGCTGGGCTGCCCCAACGGGACCGGCGCCAGCTTGAGCGACGTCTCCCCAAGGGCCTCGATGGAGGTCCGCGGGCTCATGGCCAAGCAGCTCTTGGTGACGGTTTGCCAGCGGTCTATCCACTCCACGGCGCACTGGCGGACGCGGACCGGCCCCAGGGCCGCCGCGGTGCGCAGGCCGGCGGACTCCAGCGCATGGGACGTGTCGGAGCCGGTGACCGCGAGGATGGTGTCCTTGATGACCTCCATCTCCCGGAAGGCCTGGTCGGGGGCCTCGGGGAGAGCCACCACCAAGCGGTGTACGAGCAACCCGGGGAGGTTCTCGGCCAAGAGCGCCGTCTCCGGAAGCCCGTGGGCCCGGTGGAGCGCGCACAGGTGTTCCAGCAGCGGCCGCCAGCATGCCCGCGCGTCTGCCGGGGCGATGGCCGTTCCCGACAACAGAAACGCCGCCATGGCGGCGCGCAGCTTGGCCGTGGCCAGAAACGCCGGGTCGTCCGCCCCGTTTGCCGTCTCGGCCGTGGGGGTTGGCGGTTGGCGAAGGCCGGCTAGGCTCGCCAATAGGCGCTGCATAGGTCCGTCCGAGGGCGGACCGGCGGGTGAGGTCGTGACGACGGGGGCCTCGGACGGGAGACCGCGGTCTGCCATGACGCCCGGCTCGCGTGGGTGGGGGACAGCGTAGACCAACGACGAGACCGGGCGGGAATGACTGTCGTGCGCTGTAGGGAGCGGCGAATTATCGATCCCCCGCGGCCCTCCAGGAACCCCGCAGGCGTTGCGAGTACCCCGCGTCTTCGCGGGGTGTTATACGGCCACTTAAGTCCCGGCATCCCGTTCGCGGACCCAGGCCCGGGGGATTGTCCGGATGTGCGGGCAGCCCGGACGGCGTGGGTTGCGGACTTTCGGCGGGGCGGCCCAAATGGCCCTTTAAACGTGTGTATACGGACGCGCCGGGCCAGTCGGCCAACACAACCCACCGGAGGCGGTAGCCGCGTTTGGCTGTGGGGTGGGTGGTTCCGCCTTGCGTGAGTGTCCTTTCGACCCCCCCCTCCCCCGGGTCTTGCTAGGTCGCGATCTGTGGTCGCAATGAAGACCAATCCGCTACCCGCAACCCCTTCCGTGTGGGGCGGGAGTACCGTGGAACTCCCCCCCACCACACGCGATACCGCGGGGCAGGGCCTGCTTCGGCGCGTCCTGCGCCCCCCGATCTCTCGCCGCGACGGCCCAGTGCTCCCCAGGGGGTCGGGACCCCGGAGGGCGGCCAGCACGCTGTGGTTGCTTGGCCTGGACGGCACAGACGCGCCCCCTGGGGCGCTGACCCCCAACGACGATACCGAACAGGCCCTGGACAAGATCCTGCGGGGCACCATGCGCGGGGGGGCGGCCCTGATCGGCTCCCCGCGCCATCATCTAACCCGCCAAGTGATCCTGACGGATCTGTGCCAACCCAACGCGGATCGTGCCGGGACGCTGCTTCTGGCGCTGCGGCACCCCGCCGACCTGCCTCACCTGGCCCACCAGCGCGCCCCGCCAGGCCGGCAGACCGAGCGGCTGGGCGAGGCCTGGGGCCAGCTGATGGAGGCGACCGCCCTGGGGTCGGGGCGAGCCGAGAGCGGGTGCACGCGCGCGGGCCTCGTGTCGTTTAACTTCCTGGTGGCGGCGTGTGCCGCCTCGTACGACGCGCGCGACGCCGCCGATGCGGTACGGGCCCACGTCACGGCCAACTACCGCGGGACGCGGGTGGGGGCGCGCCTGGATCGTTTTTCCGAGTGTCTGCGCGCCATGGTTCACACGCACGTCTTCCCCCACGAGGTCATGCGGTTTTTCGGGGGGCTGGTGTCGTGGGTCACCCAGGACGAGCTAGCGAGCGTCACCGCCGTGTGCGCCGGGCCCCAGGAGGCGGCGCACACCGGCCACCCGGGCCGGCCCCGCTCGGCCGTGATCCTCCCGGTGTGTGCGTTCGTGGACCTGGACGCCGAGCTGGGGCTGGGGGGCCCGGGCGCGGCGTTTCTGTACCTGGTATTCACTTACCGCCAGCGCCGGGACCAGGAGCTGTGTTGTGTGTACGTGATCAAGAGCCAGCTCCCCCCGCGCGGGTTGGAGCCGGCCCTGGAGCGGCTGTTTGGGCGCCTCCGGATCACCAACACGATTCACGGCACCGAGGACATGACGCCCCCGGCCCCAAACCGAAACCCCGACTTCCCCCTCGCGGGCCTGGCCGCCAATCCCCAAACCCCGCGTTGCTCTGCTGGCCAGGTCACGAACCCCCAGTTCGCCGACAGGCTGTACCGCTGGCAGCCGGACCTGCGGGGGCGCCCCACCGCACGCACCTGTACGTACGCCGCCTTTGCAGAGCTCGGCATGATGCCCGAGGATAGTCCCCGCTGCCTGCACCGCACCGAGCGCTTTGGGGCGGTCAGCGTCCCCGTTGTCATCCTGGAAGGCGTGGTGTGGCGCCCCGGCGAGTGGCGGGCCTGCGCGTGAGCGTAGCAAACGCCCCGCCCACACAACGCTCCGCCCCCAACCCCTTCCCCGCTGTCACTCGTTGTTCGTTGACCCGGACGTCCGCCAAATAAAGCCACTGAAACCCGAAACGCGAGTGTTGTAACGTCCTTTGGGCGGGAGGAAGCCACAAAATGCAAATGGGATACATGGAAGGAACACACCCCCGTGACTCAGGACATCGGCGTGTCCTTTTGGGTTTCACTGAAACTGGCCCGCGCCCCACCCCTGCGCGATGTGGATAAAAAGCCAGCGCGGGTGGTTTAGGGTACCACAGGTGGGTGCTTTGGAAACTTGTCGGTCGCCGTGCTCCTGTGAGCTTGCGTCCCTCCCCGGTTTCCTTTGCGCTCCCGCCTTCCGGACCTGCTCTCGCCTATCTTCTTTGGCTCTCGGTGCGATTCGTCAGGCAGTGGCCTTGTCGAATCTCGACCCCACCACTCGCCGGACCCGCCGACGTCCCCTCTCGAGCCCGCCGAAACCCGCCGCGTCTGTTGAAATGGCCAGCCGCCCCGCCGCATCCTCTCCCGTCGAAGCGCGGGCCCCGGTTGGGGGACAGGAGGCCGGCGGCCCCAGCGCAGCCACCCAGGGGGAGGCCGCCGGGGCCCCTCTCGCCCGCGGCCACCACGTGTACTGCCAGCGAGTCAATGGCGTGATGGTGCTTTCCGACAAGACGCCCGGGTCCGCGTCCTACCGCATCAGCGATAGCAACTTTGTCCAATGTGGTTCCAACTGCACCATGATCATAGACGGAGACGTGGTGCGCGGGCGCCCCCAGGACCCGGGGGCCGCGGCATCCCCCGCTCCCTTCGTTGCGGTGACAAACATCGGAGCCGGCAGCGACGGCGGGACCGCCGTCGTGGCATTCGGGGGAACCCCACGTCGCTCGGCGGGGACGTCTACCGGTACCCAGACGACCGACGTCCCCACCGAGGCCCTTGGGGGCCCCCCTCCTCCTCCCCGCTTCACCCTGGGTGGCGGCTGTTGTTCCTGTCGCGACACACGGCGCCGCTCTGCGGTATTCGGGGGGGAGGGGGATCCCGTCGGCCCCGCGGAGTTCGTCTCGGACGACCGGTCGTCCGATTCCGACTCGGATGACTCGGAGGACACCGACTCGGAGACGCTGTCACACGCCTCCTCGGACGTGTCCGGCGGGGCCACGTACGACGACGCCCTTGACTCCGATTCGTCATCGGATGACTCCCTGCAGATAGATGGCCCCGTGTGTCGCCCGTGGAGCAATGACACCGCGCCCCTGGATGTTTGCCCCGGGACCCCCGGCCCGGGCGCCGACGCCGGTGGTCCCTCAGCGGTAGACCCACACGCACCGACGCCAGGGGCCGGCGCTGGTCTTGCGGCCGATCCCGCCGTGGCCCGGGACGACGCGGAGGGGCTTTCGGACCCCCGGCCACGTCTGGGAACGGGCACGGCCTACCCCGTCCCCCTGGAACTCACGCCCGAGAACGCGGAGGCCGTGGCGCGCTTTCTGGGAGATGCCGTGAACCGCGAACCCGCGCTCATGCTGGAGTACTTTTGCCGGTGCGCCCGCGAGGAAACCAAGCGTGTCCCCCCCAGGACATTCTGCAGCCCCCCTCGCCTCACGGAGGACGACTTTGGGCTTCTCAACTACGCGCTCGTGGAGATGCAGCGCCTGTGTCTGGACGTTCCTCCGGICCCGCCGAACGCATACATGCCCTATTATCTCAGGGAGTATGTGACGCGGCTGGTCAACGGGTTCAAGCCGCTGGTGAGCCGGTCCGCTCGCCTTTACCGCATCCTGGGGGTTCTGGTGCACCTGCGGATCCGGACCCGGGAGGCCTCCTTTGAGGAGTGGCTGCGATCCAAGGAAGTGGCCCTGGACTTTGGCCTGACGGAAAGGCTTCGCGAGCACGAAGCCCAGCTGGTGATCCTGGCCCAGGCTCTGGACCATTACGACTGICTGATCCACAGCACACCGCACACGCTGGTCGAGCGGGGGCTGCAATCGGCCCTGAAGTATGAGGAGTTTTACCTAAAGCGCTTTGGCGGGCACTACATGGAGTCCGTCTTCCAGATGTACACCCGCATCGCCGGCTTTTTGGCCTGCCGGGCCACGCGCGGCATGCGCCACATCGCCCTGGGGCGAGAGGGGTCGTGGTGGGAAATGTTCAAGTTCTTTTCCACCGCCTCTACGACCACCAGATCGTACCGTCGACCCCCGCCATGCTGAACCTGGGGACCCGCAACTACTACACCTCCAGCTGCTACCTGGTAAACCCCCAGGCCACCACAAACAAGGCGACCCTGCGGGCCATCACCAGCAACGTCAGCGCCATCCTCGCCCGCAACGGGGGCATCGGGCTATGCGTGCAGGCGTTTAACGACTCCGGCCCCGGGACCGCTAGCGTCATACCCGCCCTCAAGGTCCTCGACTCGCTGGTGGCGGCGCACAACAAAGAGAGCGCGCGTCCAACCGGCGCGTGCGTGTACCTGGAGCCGTGGCACACCGACGTGCGGGCCGTGCTCCGGATGAAGGGGGTCCTCGCCGGCGAAGAGGCCCAGCGCTGCGACAATATCTTCAGCGCCCTCTGGATGCCAGACCTGTTTTTCAAGCGCCTGATTCGCCACCTGGACGGCGAGAAGAACGTCACATGGACCCTGTTCGACCGGGACACCAGCATGTCGCTCGCCGACTTTCACGGGGAGGAGTTCGAGAAGCTCTACCAGCACCTCGAGGTCATGGGGTTCGGCGAGCAGATACCCATCCAGGAGCTGGCCTATGGCATTGTGCGCAGTGCGGCCACGACCGGGAGCCCCTTCGTCATGTTCAAAGACGCGGTGAACCGCCACTACATCTACGACACCCAGGGGGCGGCCATCGCCGGCTCCAACCTCTGCACCGAGATCGTCCATCCGGCCTCCAAGCGATCCAGTGGGGTCTGCAATCTGGGAAGCGTGAATCTGGCCCGATGCGTCTCCAGGCAGACGTTTGACTTTGGGCGGCTCCGCGACGCCGTGCAGGCGTGCGTGCTGATGGTGAACATCATGATCGACAGCACGCTACAACCCACGCCCCAGTGCACCCGCGGCAACGACAACCTGCGGTCCATGGGAATCGGCATGCAGGGCCTGCACACGGCCTGCCTGAAGCTGGGGCTGGATCTGGAGTCTGTCGAATTTCAGGACCTGAACAAACACATCGCCGAGGTGATGCTGCTGTCGGCGATGAAGACCAGCAACGCGCTGTGCGTTCGCGGGGCCAGTCCCTTCAACCACTTTAAGCGCAGCATGTATCGCGCCGGCCGCTTTCACTGGGAGCGCTTTCCGGACGCCCGGCCGCGGTACGAGGGCGAGTGGGAGATGCTACGCCAGAGCATGATGAAACACGGCCTGCGCAACAGCCAGTTTGTCGCGCTGATGCCCACCGCCGCCTCGGCGCAGATCTCGGACGTCAGCGAGGGCTTTGCCCCCCTGTTCACCAACCTGTTCAGCAAGGTGACCCGGGACGGCGAGACGCTGCGCCCCAACACGCTCCTGCTAAAGGAACTGGAACGCACGTTTAGCGGGAAGCGCCTCCTGGAGGTGATGGACAGTCTCGACGCCAAGCAGTGGTCCGTGGCGCAGGCGCTCCCGTGCCTGGAGCCCACCCACCCCCTCCGGCGATTCAAGACCGCGTTTGACTACGACCAGAAGTTGCTGATCGACCTGTGTGCGGACCGCGCCCCCTACGTCGACCATAGCCAATCCATGACCCTGTATGTCACGGAGAAGGCGGACGGGACCCTCCCAGCCTCCACCCTGGTCCGCCTTCTGGTCCACGCATATAAGCGCGGACTAAAAACAGGGATGTACTACTGCAAGGTTCGCAAGGCGACCAACAGCGGGGTCTTTGGCGGCGACGACAACATTGTCTGCACGAGCTGCGCGCTGTGCCCGACAACCCCCTCCGCGCCAGGCCCGCCGCCACTGTCGTCGCCGTCCCACGCGCTCCCCCGCTGCCATGGATTCCGCGGCCCCAGCCCTCTCCCCCGCTCTGACGGCCCATACGGGCCAGAGCACGCCGGCGGACCTGGCGATCCAGATTCCAAAGTGCCCCGACCCCGAGAGGTACTTCTACACCTCCCAGTGTCCCGACATTAACCACCTGCGCTCCCTCAGCATCCTTAACCGCTGGCTGGAAACCGAGCTTGTTTTCGTGGGGGACGAGGAGGACGTCTCCAAGCTTTCCGAGGGCGAGCTCAGCTTTTACCGCTTCCTCTTCGCTTTCCTGTCGGCCGCCGACGACCTGGTTACGGAAAACCTGGGCGGCCTCTCCGGCCTGTTTGAGCAGAAGGACATTCTCCACTACTACGTGGAGCAGGAATGCATCGAAGTCGTACACTCGCGCGTGTACAACATCATCCAGCTGGTGCTTTTTCACAACAACGACCAGGCGCGCCGCGAGTACGTGGCCGGCACCATCAACCACCCGGCCATCCGCGCCAAGGTGGACTGGCTGGAAGCGCGGGTGCGGGAATGCGCCTCCGTTCCGGAAAAGTTCATCCTCATGATCCTCATCGAGGGCATCTTTTTTGCCGCCTCGTTTGCCGCCATCGCCTACCTTCGCACCAACAACCTTCTGCGGGTCACCTGCCAGTCAAACGACCTCATCAGCCGGGACGAGGCCGTGCACACGACGGCCTCGTGTTACATCTACAACAACTACCTCGGCGGGCACGCCAAGCCCCCGCCCGACCGCGTGTACGGGCTGTTCCGCCAGGCGGTCGAGATCGAGATCGGATTTATCCGATCCCAGGCGCCGACGGACAGCCATATCCTGAGCCCGGCGGCGCTGGCGGCCATCGAAAACTACGTGCGATTCAGCGCGGATCGCCTGTTGGGCCTTATCCACATGAAGCCACTGTTTTCCGCCCCACCCCCCGACGCCAGCTTTCCGCTGAGCCTCATGTCCACCGACAAACACACCAATTTTTTCGAGTGTCGCAGCACCTCCTACGCCGGGGCGGTCGTCAACGATCTGTGAGGGTCGCGGCGCGCTTCTACCCGTGTTTGCCCATAATAAACCTCTGAACCAAACTTTGGGTCTCATTGTGATTCTTGTCAGGGACGCGGGGGTGGGAGAGGATAAAAGGCGGCGCAAAAAGCAGTAACCAGGTCCGTCCAGATTCTGAGGGCATAGGATACCATAATTTTATTGGTGGGTCGTTTGTTCGGGGACAAGCGCGCTCGTCTGACGTTTGGGCTACTCGTCCCAGAATTTGGCCAGGACGTCCTTGTAGAACGCGGGTGGGGGGGCCTGGGTCCGCAGCTGCTCCAGAAACCTGTCGGCGATATCAGGGGCCGTGATATGCCGGGTCACAATAGATCGCGCCAGGTTTTCGTCGCGGATGTCCTGGTAGATAGGCAGGCGTTTCAGAAGAGTCCACGGCCCCCGCTCCTTGGGGCCGATAAGCGATATGACGTACTTAATGTAGCGGTGTTCCACCAGCTCGGTGATGGTCATGGGATCGGGGAGCCAGTCCAGGGACTCTGGGGCGTCGTGGATGACGTGGCGTCGCCGGCTGGCCACATAACTGCGGTGCTCTTCCAGCAGCTGCGCGTTCGGGACCTGGACGAGCTCGGGCGGGGTGAGTATCTCCGAGGAGGACGACCTGGGGCCGGGGTGGCCCCCGGTAACGTCCCGGGGATCCAGGGGGAGGTCCTCGTCGTCTTCGTATCCGCCGGCGATCTGTTGGGTTAGAATTTCGGTCCACGAGACGCGCATCTCGGTGCCGCCGGCGGCCGGCGGCAAAGGGGGCCTGGTTTCCGTGGAGCGCGAGCTGGTGTGTTCCCGGCGGATGGCCCGCCGGGTCTGAGAGCGACTCGGGGGGGTCCAGTGACATTCGCGCAGCACATCCTCCACGGAGGCGTAGGTGTTATTGGGATGGAGGTCGGTGTGGCAGCGGACAAAGAGGGCCAGGAACTGGGGGTAGCTCATCTTAAAGTACTTTAGTATATCGCGACAGTTGATCGTGGGAATGTAGCAGGCGCTAATATCCAACACAATATCACAGCCCATCAACAGGAGGTCAGTGTCTGTGGTGTACACGTACGCGACCGTGTTGGTGTGATAGAGGTTGGCGCAGGCATCGTCCGCCTCCAGCTGACCCGAGTTAATGTAGGCGTACCCCAGGGCCCGGAGAACGCGAATACAGAACAGATGCGCCAGACGCAGGGCCGGCTTCGAGGGCGCGGCGGACGGCAGCGCGGCTCCGGACCCGGCCGTCCCCCGGGTCCCCGAGGCCAGAGAGGTGCCGCGCCGGCGCATGTTGGAAAAGGCAGAGCTGGGTCTGGAGTCGGTGATGGGGGAAGGCGGTGGAGAGGCGTCCACGTCACTGGCCTCCTCGTCCGTCCGGCATTGGGCCGTCGTGCGGGCCAGGATGGCCTTGGCTCCAAACACAACCGGCTCCATACAATTGACCCCGCGATCGGTAACGAAGATGGGGAAAAGGGACTTTTGGGTAAACACCTTTAATAAGCGACAGAGGCAGTGTAGCGTAATGGCCTCGCGGTCGTAACTGGGGTATCGGCGCTGATATTTGACCACCAACGTGTACATGACGTTCCACAGGTCCACGGCGATGGGGGTGAAGTACCCGGCCGGGGCCCCAAGGCCCTGGCGCTTGACCAGATGGTGTGTGTGGGCAAACTTCATCATCCCGAACAAACCCATGTCAGGTCGATTGTAACTGCGGATCGGCCTAACTAAGGCGTGGTTGGTGCGACGGTCCGGGACACCCGAGTCTGTCTCTCTGTGTATGGTGACCCAGACAACAACACCGACACAAGAGGACAATAATCCGTTAGGGGACGCTCTTTATAATTTCGATGGCCCAACTCCACGCGGATTGGTGCAGCACCCTGCATGCGCCGGTGTGGGCCAAACTTCCCCCCGCTCATTGCCTCTTCCAAAAGGGTGTGGCCTAACGAGCTGGGGGCGTATTTAATCAGGCTAGCGCGGCGGGCCTGCCGTAGTTTCTGGCTCGGTGAGCGACGGTCCGGTTGCTTGGGTCCCCTGGCTGCCAGCAAAACCCCACCCTCGCAGCGGCATACGCCCCCTCCGCGTCCCGCACCCGAGACCCCGGCCCGGCTGCCCTCACCACCGAAGCCCACCTCGTCACTGTGGGGTGTTCCCAGCCCGCATTGGGATGACGGATTCCCCTGGCGGTGTGGCCCCCGCCTCCCCCGTGGAGGACGCGTCGGACGCGTCCCTCGGGCAGCCGGAGGAGGGGGCGCCCTGCCAGGTGGTCCTGCAGGGCGCCGAACTTAATGGAATCCTACAGGCGTTTGCCCCGCTGCGCACGAGCCTTCTGGACTCGCTTCTGGTTATGGGCGACCGGGGCATCCTTATCCATAACACGATCTTTGGGGAGCAGGTGTTCCTGCCCCTGGAACACTCGCAATTCAGTCGGTATCGCTGGCGCGGACCCACGGCGGCGTTCCTGTCTCTCGTGGACCAGAAGCGCTCCCTCCTGAGCGTGTTTCGCGCCAACCAGTACCCGGACCTACGTCGGGTGGAGTTGGCGATCACGGGCCAGGCCCCGTTTCGCACGCTGGTTCAGCGCATATGGACGACGACGTCCGACGGCGAGGCCGTTGAGCTAGCCAGCGAGACGCTGATGAAGCGCGAACTGACGAGCTTTGTGGTGCTGGTTCCCCAGGGAACCCCCGACGTTCAGTTGCGCCTGACGAGGCCGCAGCTCACCAAGGTCCTTAACGCGACCGGGGCCGATAGTGCCACGCCCACCACGTTCGAGCTCGGGGTTAACGGCAAATTTTCCGTGTTCACCACGAGTACCTGCGTCACATTTGCTGCCCGCGAGGAGGGCGTGTCGTCCAGCACCAGCACCCAGGTCCAGATCCTGTCCAACGCGCTCACCAAGGCGGGCCAGGCGGCCGCCAACGCCAAGACGGTGTACGGGGAAAATACCCATCGCACCTTCTCTGTGGTCGTCGACGATTGCAGCATGCGGGCGGTGCTCCGGCGACTGCAGGTCGCCGGGGGCACCCTCAAGTTCTTCCTCACGACCCCCGTCCCCAGTCTGTGCGTCACCGCCACCGGTCCCAACGCGGTATCGGCGGTATTTCTCCTGAAACCCCAGAAGATTTGCCTGGACTGGCTGGGTCATAGCCAGGGGTCTCCTTCAGCCGGGAGCTCGGCCTCCCGGGCCTCTGGGAGCGAGCCAACAGACAGCCAGGACTCCGCGTCGGACGCGGTCAGCCACGGCGATCCGGAAGACCTCGATGGCGCTGCCCGGGCGGGAGAGGCGGGGGCCTCGCACGCCTGTCCGATGCCGTCGTCGACCACGCGGGTCACTCCCACGACCAAGCGGGGGCGCTCGGGGGGCGAGGATGCGCGCGCGGACACGGCCCTAAAGAAACCTAAGACGGGGTCGCCCACCGCACCCCCGCCCACAGATCCAGTCCCCCTGGACACGGAGGACGACTCCGATGCGGCGGACGGGACGGCGGCCCGTCCCGCCGCTCCAGACGCCCGGAGCGGAAGCCGTTACGCGTGTTACTTTCGCGACCTCCCGACCGGAGAAGCAAGCCCCGGCGCCTTCTCCGCCTTCCGGGGGGGCCCCCAAACCCCGTATGGTTTTGGATTCCCCTGACGGGGCGGGGCCTTGGCGGCCGCCCAACTCTCGCACCATCCCGGGTTAATGTAAATAAACTTGGTATTGCCCAACACTCTCCCGCGTGTCGCGTGTGGTTCATGTGTGTGCCTGGCGTCCCCCACCCTCGGGTTCGTGTATTTCCTTTCCCTGTCCTTATAAAAGCCGTATGTGGGGCGCTGACGGAACCACCCCGCGTGCCATCACGGCCAAGGCGCGGGATGCTCCGCAACGACAGCCACCGGGCCGCGTCCCCGGAGGACGGCCAGGGACGGGTCGACGACGGACGGCCACACCTCGCGTGCGTGGGGGCCCTGGCGCGGGGGTTCATGCATATCTGGCTTCAGGCCGCCACGCTGGGTTTTGCGGGATCGGTCGTTATGTCGCGCGGGCCGTACGCGAATGCCGCGTCTGGGGCGTTCGCCGTCGGGTGCGCCGTGCTGGGCTTTATGCGCGCACCCCCTCCCCTCGCGCGGCCCACCGCGCGGATATACGCCTGGCTCAAACTGGCGGCCGGTGGAGCGGCCCTTGTTCTGTGGAGTCTCGGGGAGCCCGGAACGCAGCCGGGGGCCCCGGGCCCGGCCACCCAGTGCCTGGCGCTGGGCGCCGCCTATGCGGCGCTCCTGGTGCTCGCCGATGACGTCTATCCGCTCTTTCTCCTCGCCCCGGGGCCCCTGTTCGTCGGCACCCTGGGGATGGTCGTCGGCGGGCTGACGATCGGAGGCAGCGCGCGCTACTGGTGGATCGGTGGGCCCGCCGCGGCCGCCTTGGCCGCGGCGGTGTTGGCGGGCCCGGGGGCGACCACCGCCAGGGACTGCTTCTCCAGGGCGTGCCCCGACCACCGCCGCGTCTGCGTCATCGTCGCAGGCGAGTCTGTTTCCCGCCGCCCCCCGGAGGACCCAGAGCGACCCGGGGACCCCGGGCCACCGTCCCCCCCGACACCCCAACGATCCCAGGGGCCGCCGGCCGATGAGGTCGCACCGGCCGGGGTAGCGCGGCCCGAAAACGTCTGGGTGCCCGTGGTCACCTTTCTGGGGGCGGGCGCGCTCGCCGTCAAGACGGTGCGAGAACATGCCCGGGAAACGCCGGGCCCGGGCCTGCCGCTGTGGCCCCAGGTGTTTCTCGGAGGCCATGTGGCGGTGGCCCTGACGGAGCTGTGTCAGGCGCTTATGCCCTGGGACCTTACGGACCCGCTGCTGTTTGTTCACGCCGGACTGCAGGTCATCAACCTCGGGTTGGTGTTTCGGTTTTCCGAGGTTGTCGTGTATGCGGCGCTAGGGGGTGCCGTGTGGATTTCGTTGGCGCAGGTGCTGGGGCTCCGGCGTCGCCTGCACAGGAAGGACCCCGGGGACGGGGCCCGGTTGGCGGCGACGCTTCGGGGCCTCTTCTTCTCCGTGTACGCGCTGGGGTTTGGGGTGGGGGCGCTGCTGTGCCCTCCGGGGTCAACGGGCGGGTGGTCGGGCGATTGATATATTTTTCAATAAAAGGCATTAGTCCCGAAGACCGCCGGTGTGTGATGATTTCGCCATAACACCCAAACCCCGGATGGGGCCCGGGTATAAATTCCGGAAGGGGACACGGGCTACCCTCACTACCGAGGGCGCTTGGTCGGGAGGCCGCATCGAACGCACACCCCCATCCGGTGGTCCGTGTGGAGGTCGTTTTTCAGTGCCCGGTCTCGCTTTGCCGGGAACGCTAGCCGATCCCTCGCGAGGGGGAGGCGTCGGGCATGGCCCCGGGGCGGGTGGGCCTTGCCGTGGTCCTGTGGAGCCTGTTGTGGCTCGGGGCGGGGGTGGCCGGGGGCTCGGAAACTGCCTCCACCGGGCCCACGATCACCGCGGGAGCGGTGACGAACGCGAGCGAGGCCCCCACATCGGGGTCCCCCGGGTCAGCCGCCAGCCCGGAAGTCACCCCCACATCGACCCCAACCCCCAACAATGTCACACAAAACAAAACCACCCCCACCGAGCCGGCCAGCCCCCCAACAACCCCCAAGCCCACCTCCACGCCCAAAAGCCCCCCCACGTCCCCCCGCCCCAACCCAAGAACAACACCCCCCCCGCCAAGTCGGGCCGCCCCACTAAACCCCCCGGGCCCGTGTGGTGCGACCGCCGCGACCCATTGGCCCGGTACGGCTCGCGGGTGCAGATCCGATGCCGGTTTCGGAATTCCACCCGCATGGAGTTCCGCCTCCAGATATGGCGTTACTCCATGGGTCCGTCCCCCCCAATCGCTCCGGCTCCCGACCTAGAGGAGGTCCTGACGAACATCACCGCCCCACCCGGGGGACTCCTGGTGTACGACAGCGCCCCCAACCTGACGGACCCCCACGTGCTCTGGGCGGAGGGGGCCGGCCCGGGCGCCGACCCTCCGTTGTATTCTGTCACCGGGCCGCTGCCGACCCAGCGGCTGATTATCGGCGAGGTGACGCCCGCGACCCAGGGAATGTATTACTTGGCCTGGGGCCGGATGGACAGCCCGCACGAGTACGGGACGTGGGTGCGCGTCCGCATGTTCCGCCCCCCGTCTCTGACCCTCCAGCCCCACGCGGTGATGGAGGGTCAGCCGTTCAAGGCGACGTGCACGGCCGCCGCCTACTACCCGCGTAACCCCGTGGAGTTTGTCTGGTTCGAGGACGACCGCCAGGTGTTTAACCCGGGCCAGATCGACACGCAGACGCACGAGCACCCCGACGGGTTCACCACAGTCTCTACCGTGACCTCCGAGGCTGTCGGCGGCCAGGTCCCCCCGCGGACCTTCACCTGCCAGATGACGTGGCACCGCGACTCCGTGATGTTCTCGCGACGCAATGCCACCGGGCTGGCCCTGGTGCTGCCGCGGCCAACCATCACCATGGAATTTGGGGICCGGCATGTGGTCTGCACGGCCGGCTGCGTCCCCGAGGGCGTGACGTTTGCCTGGTTCCTGGGGGACGACCCCTCACCGGCGGCTAAGTCGGCCGTTACGGCCCAGGAGTCGTGCGACCACCCCGGGCTGGCTACGGTCCGGTCCACCCTGCCCATTTCGTACGACTACAGCGAGTACATCTGTCGGTTGACCGGATATCCGGCCGGGATTCCCGTTCTAGAGCACCACGGCAGTCACCAGCCCCCACCCAGGGACCCCACCGAGCGGCAGGTGATCGAGGCGATCGAGTGGGTGGGGATTGGAATCGGGGTTCTCGCGGCGGGGGTCCTGGTCGTAACGGCAATCGTGTACGTCGTCCGCACATCACAGTCGCGGCAGCGTCATCGGCGGTAACGCGAGACCCCCCCGTTACCTTTTTAATATCTATATAGTTTGGTCCCCCTCTATCCCGCCCACCGCTGGGCGCTATAAAGCCGCCACCCTCTCTTCCCTCAGGICATCCTTGGTCGATCCCGAACGACACACGGCGTGGAGCAAAACGCCTCCCCCTGAGCCGCTTTCCTACCAACACAACGGCATGCCTCTGCGGGCATCGGAACACGCCTACCGGCCCCTGGGCCCCGGGACACCCCCCATGCGGGCTCGGCTCCCCGCCGCGGCCTGGGTTGGCGTCGGGACCATCATCGGGGGAGTTGTGATCATTGCCGCGTTGGTCCTCGTGCCCTCGCGGGCCTCGTGGGCACTTTCCCCATGCGACAGCGGATGGCACGAGTTCAACCTCGGGTGCATATCCTGGGATCCGACCCCCATGGAGCACGAGCAGGCGGTCGGCGGCTGTAGCGCCCCGGCGACCCTGATCCCCCGCGCGGCTGCCAAACAGCTGGCCGCCGTCGCACGCGTCCAGTCGGCAAGATCCTCGGGCTACTGGTGGGTGAGCGGAGACGGCATTCGGGCCTGCCTGCGGCTCGTCGACGGCGTCGGCGGTATTGACCAGTTTTGCGAGGAGCCCGCCCTCGCATATGCTACTATCCCCGCAGTCCCGGGGGCTTTGTTCAGTTTGTAACTTCGACCCGCAACGCGCTGGGGCTGCCGTGAGGCGCGTGTACTGCGGTCTGTCTCGTCTCCTCTTCTCCCCTTCCCTCCCCCTCCGCATCCCAGGATCACACCGGCCAACGAGGGTTGGGGGGGTCCGGCACGGACCCAAAATAATAAACACACAATCACGTGCGATAAAAAGAACACGCGGTCCCCTGTGGTGTTTTTGGTTATTTTTATTAAATCTCGTCGACAAACAGGGGGAAAGGGGCGTGGTCTAGCGACGGCAGCACGGGCGGAGGCGTTCACCGGCTCCGGCGTCCTTCGCGTTTAAGCTTGGTCAGGAGGGCGCTCAGGGCGGCGACGTTGGTCGGGCCGTCGTTGGTCAGGGCGTTGGCTCGATGGCGGGCGAGGACGGGCGAGGGGCTCAACGGCGGGGGCGGGGGCCGGGGCGGCCCGGGGGGGGAAATAGGGCGGATCCCCCCCCGTCGTACAGGGGGTTTTCCGCCTCAATGTACGGGGAGGCCGGCGCTGCATTCGCCGTGTTCACGCAGACGGTTTCGTAGACCCGCATCCATGGTATTTCCTCGTAGACACGCCCCCCGTCCTCGCTCACGGTCTCGTATATTGACTCGTCGTCCTCGTAGGGGGCGTGCCGTTCGCGGGCCGAGGCGGCGTGGGTGGCTTTGCGGCGGGCGTCGTCGTCGTCGTCGTCGGCCGTCAGATACGTGGCTTCCATCTGGTCGGGTTCTCCCTCCGGGGCGGGTCCCCACACCCGTGGCCGATCGAGGCTCCCCAGAGACGCGCGCCGGACAAGAAGGGGGCACGTCGCCGCCGGCGGTCGCCTGTCGGGTCCCGCGACGTTACGGGCCGGGAGGCGCGGGGGCACCTCCCCCATGTGCGTGTAATACGTGGCCGGCTGTGCGGCCGCAGCGGGGGGCTCGGCGACCGGGTCGTCCGCATCCGGAAGCGGGGGCCCCGCGCCGTCCGCACGGCGCCTCCGGAACCGCCGGGTGGACGGCGCGGGGGTCGAGTGTAGGCGAGGTCGGGGGAGGGGCGGGGGCTCGTTGTCGCGCCGCGCCCGCTGAATCTTTTCCCGACAGGTCCCACCCCCCGCGCGATGCCCCCCCGGGCCGCGGGCCATGTCGTCCGGGGGAGGCCCCGCGGACCACGTCGTCCGGCGAGACGCCACGAGCCGCAGGATGGACTCGTAGTGGAGCGACGGCGCCCCGCTGCGGAGCAGATCCGCGGCCAGGGCGGCCCCGAACCAAGCCTTGATGCTCAACTCCATCCGGGCCCAGCTGGGGGCGGTCATCGTGGGGAACAGGGGGGCGGTGGTCCGACAGAAACGCTCCTGGCTGTCCACCGCGGCCCGCAGATACTCGTTGTTCAGGCTGTCGGTGGCCCAGACGCCGTACCCGGTGAGGGTCGCGTTGATGATATACTGGGCGTGGTGATGGACGATCGACAGAACCTCCACCGTGGATACCACGGTATCCACGGTCCCGTACGTACCGCCGCTCCGCTTGCCGGTCTGCCACAGGTTGGCTAGGCACGTCAGGTGGCCCAGGACGTCGCTGACCGCCGCCCTGAGCGCCATGCACTGCATGGAGCCGGTCGTGCCGCTGGGACCCCGGTCCAGATGGCGCGCGAACGTTTCCGCGGGCGCCTCCGGGCTGCCGCCGAGCGGGAGGAACCGGCGATTGGAGGGACTCAGCCGGTGACATACGTGCTTGTCCGTCGTCCACAGCATCCAGGACGCCCACCGGTACAGCACGGAGACGTAGGCCAGGAGCTCGTTGAGCCGCAGTGCGGTGTCGGTGCTGGGGCGGCTTGGGTCCGCCGGGCGCATAAAGAACATGTACTGCTGAATCCGATGGAGGGCGTCGCGCAGGCCGGCCACGGTGGCGGCGTACTTGGCCGCCGCGGCCCCGCTCTTGAACGGGGTGCGCGCCAGCAGCTTTGGCGCCAGGGTGGGCCGCAGCAGCACGTGAAGGCTGGGGTCGCAGTCGCCCACGGGGTCCTCGGGGACGTCCAGGCCGCTGGGCACCACCGTCTGCAGGTACTTCCAGTACTGCGTGAGGATGGCGCGGCTCAACTGGCCGCCGGGCAGCTCCACCTCGCCCAGCGCCTGGGTGGCGGCCGAAGCGTAGTGCCGGATGTACTCGTAGTGCGGGTCGCTGGCGAGCCCGTCCACGATCAAACTCTCGGGAACCGTGTTGTGTTGCCGCGCGGCCAACCGGACGCTGCGATCGGTGCAGGTCAGAAACGCCGGCTGCGCGTCGTCGGAGCGCTGCCGCAAGGCGCCCACGGCCGCGCTAAGGAGCCCCTCCGGGGTGGGGAGCAGACACCCGCCGAAGATGCGCCGCTCGGGAACGCCCGCGTTGTCGCCGCGGATCAGGTTGGCAGGCGTCAGGCACCGCGCCAGCCGCAGGGAGCTCGCGCCGCGCGTCCGGCGCTGCATGGTGACGCCCGTTCGGTCGGGACCCGCCGGTCGGAGTTATGCCGCGTCCAGGGCCATCGGGGCGCTTTTTATCGGGAGGAGCTTATGGGCGTGGCGGGCCTCCCAGCCCGGTCGCGCGCCTCCCCGACACGTGCGCCCGCAGGGCGGCGGCCCCCTCGTCTCCCATCAGCAGTTTCCTAAACTGGGACATGATGCCACCCGCGGACCCGCGGGCCAACACGGACCCGCCGCTTACGGGGGCGGGGGGGAAGGGCTCCAGGTCCTTGAGCAGAAAGGCGGGGTCTGCCGTCCCGGACACGGGGGCCCGGGGCGCGGAGGAGGCGGGGCGCAGATCCACGTGCTCCGCGGCCGCGCGGACGTCCGCCCAGAACTTGGCGGGGGTGGTGCGCGCGTACAGGGGCTGGGTCGCTCGGAGGACACACGCGTAGCGCAGGGGGGTGTACGTGCCCACCTCGGGGGCCGTGAATCCCCCGTCAAACGCGGCCAGTGTCACGCACGCCACCACGGTGTCGGCAAAACCCAGCAGCCGCTGCAGGACGAGCCCGGCGGCCAGAATGGCGCGCGTGGTCGCAGCGTCGTCCCGGCGCCGGTGCGCGTCCCCGCACGCCCGGGCGTACTTTAAGGTCACTGTCGCCAGGGCCGTGTGCAGCGCGTACACCGCAGCGCCCAGCACGGCGTTGAGCCCGCTGTTGGCGAGCAGCCGGCGCGCTGCGGTGTCGCCCAGCGCCTCGTGCTCGGCCCCCACGACCGCGGGGCTTCCCAGGGGCAGGGCGCGAAACAGCTCCTCCCGCGCCACGTCCGCAAAGGCGGGGTGGTGCACGTGCGGGTGCAGGCGCGCCCCCACGACCACCGAGAGCCACTGGACCGTCTGCTCCGCCATCACCGCCAACACATCCAGCACGCGCCCCAGGAAGGCGGCCTCCCGCGTCAAAACGCACCGGACGGCGTCGGGATTGAAGCGGGCGAGCAGGGCCCCGGTGGCCAGGTACGTCATGCGGCCGGCATAGCGGGCGGCCACGCGACAGTCGCGGTCCAGCAGCGCGCGCACCCCGGGCCAGTACAGCAGGGACCCCAGCGAGCTGCGAAACACCGCGGCGTCGGGGCCGGATTGGGGGGACACTAACCCCCCCGCGCTCAGTAACGGCACGGCCGCGGCCCCGACGGGACGCAACGCCGTGAGGCTCGCGAACTGCCGCCTCAGCTCGGCAGCCCTGTCGTCCAGGTCCGACCCGCGCGCCTCTGCGTGAAGGCGCGTCCCGCATACCCACCCGTTGATGGCCAGCCGCACGACGGCATCCGCCAAAAAGCTCATCGCCTGGGCGGGGCTGGTTTTTGTTCGACGATCCGTCAGGTCAAGAATCCCATCGCCCGTGATATACCAGGCCAACGCCTCGCCCTGCTGCAGGGTTTGGCGGAAAAACACCGCGGGGTTGTCGGGGGAGGCGAAGTGCATGACCCCCACGCGCGATAACCCGAACGCGCTATCCGGACACGGGTAAAACCCGGCCGGATGCCCCAGGGCTAGGGCGGAGCGCACGGACTCGTCCCACACGGCAACCTGAGGGGCCAGTCGATCCAACGGGAATGCCGCCCGGAGCTCCGGGCCCGGCACGCGTCCCTCCAGAACCTCCACCTTGGGCGGGGAACGGGCCCCGCCGCCGTCCTCCGGCCCGACGTCTTCCGGGTAGTCGTCCTCCTCGTACTGCAGTTCCTCTAGGAACAGCGGCGACGGCGCCACCCGCGAACCGCCGACCCGCCCCAAAATAGCCCGCGCGTCGACGGGACCCAGGTATCCCCCCTGCCGGGCCTGCGGAGGACCGCGGGGAACCTCATCATCATCGTCCAGGCGACCGCGCACCGACTGGCTACGGGCCGCATCGGGCCCGGGGCGCTGCCGGGACGCTCGGCGATGGGATGAGGGCGGGGCTTCCGACGCGCGCCGTCGTCGGGCTCGCGGGCCTTCCCGTCGACGGCGCACGGGCGGCTCGTCGCCCGCCATCTCCTCCAGAGCCTCTAGCTCGCTGTCGTCATCCCCGCGGAACACCGCACGCAGGTACCCCATGAACCCCACCCCATCGCCCGCTGGCTCGTCCGCCACGGGCGAGGCGCGGGGGCGGGTGGATGCGCGCCTCCTGCGCCCCGCGGGTTCGCGAGCCGACATGGTGGCGATAGACGCGGGTTATCGGATGTCCGCTACCCCCCAAAAAAGAAAAAGACCCCACAGCGCGGATGGAGGTCGGGGTAGGTGCCGCCGGACCCCCTCGCGATGGGAATGGACGGGAGCGACGGGGCCGGCGCAAAAAACGCAGTATCTCCCGCGAAGGCTACCCGCCGCCCCAGCCCCCGGCCAAATGCGGAAACGGTCCCGCGCTCTCGCCTTTATACGCGGGCCGCCCTGCGACACAATCACCCGTCCGTGGTTTCGAATCTACACGACAGGCCCGCAGACGCGGCTAACACACACGCCGGCAACCCAGACCCCAGTGGGTTGGTTGCGCGGTCCCGTCTCCTGGCTAGTTCTTTCCCCCACCACCAAATAATCAGACGACAACCGCAGGTTTTTGTAATGTATGTGCTCGTGTTTATTGTGGATACGAACCGGGGACGGGAGGGGAAAACCCAGACGGGGGATGCGGGTCCGGTCGCGCCCCCTACCCACCGTACTCGTCAATTCCAAGGGCATCGGTAAACATCTGCTCAAACTCGAAGTCGGCCATATCCAGAGCGCCGTAGGGGGCGGAGTCGTGGGGGGTAAATCCCGGACCCGGGGAATCCCCGTCCCCCAACATGTCCAGATCGAAATCGTCTAGCGCGTCGGCATGCGCCATCGCCACGTCCTCGCCGTCTAAGTGGAGCTCGTCCCCCAGGCTGACATCGGTCGGGGGGGCCGTCGACAGTCTGCGCGTGTGTCCCGCGGGGAGAAAGGACAGGCGCGGAGCCGCCAGCCCCGCCTCTTCGGGGGCGTCGTCGTCCGGGAGATCGAGCAGGCCCTCGATGGTAGACCCGTAATTGTTTTTCGTACGCGCGCGGCTGTACGCGTGTTCCCGCATGACCGCCTCGGAGGGCGAGGTCGTGAAGCTGGAATACGAGTCCAACTTCGCCCGAATCAACACCATAAAGTACCCAGAGGCGCGGGCCTGGTTGCCATGCAGGGTGGGAGGGGTCGTCAACGGCGCCCCTGGCTCCTCCGTAGCCGCGCTGCGCACCAGCGGGAGGTTAAGGTGCTCGCGAATGTGGTTTAGCTCCCGCAGCCGGCGGGCCTCGATTGGCACTCCCCGGACGGTGAGCGCTCCGTTGACGAACATGAAGGGCTGGAACAGACCCGCCAACTGACGCCAGCTCTCCAGGTCGCAACAGAGGCAGTCAAACAGGTCGGGCCGCATCATCTGCTCGGCGTACGCGGCCCATAGGATCTCGCGGGTCAAAAATAGATACAAATGCAAAAACAGAACACGCGCCAGACGAGCGGTCTCTCGGTAGTACCTGTCCGCGATCGTGGCGCGCAGCATTTCTCCCAGGTCGCGATCGCGTCCGCGCATGTGCGCCTGGCGGTGCAGCTGCCGGACGCTGGCGCGCAGGTACCGGTACAGGGCCGAGCAGAAGTTGGCCAACACGGTTCGATAGCTCTCCTCCCGCGCCCGTAGCTCGGCGTGGAAGAAACGAGAGAGCGCTTCGTAGTAGAGCCCGAGGCCGTCGCGGGTGGCCGGAAGCGTCGGGAAGGCCACGTCGCCGTGGGCGCGAATGTCGATTTGGGCGCGTTCGGGGACGTACGCGTCCCCCCATTCCACCACATCGCTGGGCAGCGTTGATAGGAATTTACACTCCCGGTACAGGTCGGCGTTGGTCGGTAACGCCGAAAACAAATCCTCGTTCCAGGTATCGAGCATGGTACATAGCGCGGGGCCCGCGCTAAAGCCCAAGTCGTCGAGGAGACGGTTAAAGAGGGCGGCGGGGGGGACGGGCATGGGCGGGGAGGGCATGAGCTGGGCCTGGCTCAGGCGCCCCGTTGCGTACAGCGGAGGGGCCGCCGGGGTGTTTTTGGGACCCCCGGCCGGGCGGGGGGGTGGTGGCGAAGCGCCGTCCGCGTCCATGTCGGCAAACAGCTCGTCGACCAAGAGGTCCATTGGGTGGGGTTGATACGGGAAAGACGATATCGGGCTTTTGATGCGATCGTCCCCGCCCGCCCAGAGAGTGTGGGACGCCCGACGGCGCGGGAAGAGAAAAACCCCCAAACGCGTTAGAGGACCGGACGGACCTTATGGGGGGAAGTGGGCAGCGGGAACCCCGTCCGTTCCCGAGGAATGACAGCCCGTGGTCGCCACCCCGCATTTAAGCAACCCGCACGGGCCGCCCCGTACCTCGTGACTTCCCCCCACATTGGCTCCTGTCACGTGAAGGCAAACCGAGGGCGGCTGTCCAACCCACCCCCCGCCACCCAGTCACGGTCCCCGTCGGATTGGGAAACAAAGGCACGCAACGCCAACACCGAATGAACCCCTGTTGGTGCTTTATTGTCTGGGTACGGAAGTTTTTCACTCGACGGGCCGTCTGGGGCGAGAAGCGGAGCGGGCTGGGGCTCGAGGTCGCTCGGTGGGGCGCGACGCCGCAGAACGCCCTCGAGTCGCCGTGGCCGCGTCGACGTCCTGCACCACGTCTGGATTCACCAACTCGTTGGCGCGCTGAATCAGGTTTTTGCCCTCGCAGACCGTCACGCGGATGGTGGTGATGCCAAGGAGTTCGTTGAGGTCTTCGTCTGTGCGCGGACGCGACATGTCCCAGAGCTGGACCGCCGCCATCCGGGCATGCATGGCCGCCAGGCGCCCAACCGCGGCGCAGAAGACGCGCTTGTTAAAGCCGGCCACCCGGGGGGTCCATGGCGCGTCGGGGTTTGGGGGGGCGGTGCTAAAGTGCAGCTTTCTGGCCAGCCCCTGCGCGGGTGTCTTGGATCGGGTTGGCGCCGTCGACGCGGGGGCGTCTGGGAGTGCGGCGGATTCTGGCTGGGCCGATTTCCTGCCGCGGGTGGTCTCCGCCGCCGGGGCCGCGGGGGCCTTAGTCGCCACCCGCTGGGTTCGGGGGGCCCGGGGGGCGGTGGTGGGTGTGCGTCCGGCCCCTCCGGACCCAGCGGGCGGCGGAGGCGCCCGCGCAGGCCCCGGGGCGGACAAAACCGCCCCGGAAACGGGACGCCGCGTCCGGGGGACCTCCGGGTGTTCGTCGTCTTCGGATGACGAGCCCCCGTAGAGGGCATAATCCGACTCGTCGTACTGGACGAAACGGACCTCGCCCCTTGGGCGCGCGCGTGTCTGTAGGGCGCCACGGCGGGAGGTGTCAGGCGGACTATCGGGACTCGCCATACATGAAGACGGGGTGTAGTACAGATCCTCGTACTCATCGCGCGGAACCTCCCGCGGACCCGACTTCACGGAGCGGCGAGAGGTCATGGTTCCACGAACACGCTAGGGTCGGATGCGCGGACAATTAGGCCTGGGTTCGGACGGCGGGGGTGGTGCAGGTGTGGAGAGGTCGAGCGATAGGGGCGGCCCGGGAGAGAAGAGAGGGTCCGCAAAACCCACTGGGGATGCGTGAGIGGCCCTCTGTGGGCGGTGGGGGAGAGTCTTATAGGAAGTGCATATAACCACAACCCATGGGTCTAACCAATCCCCAGGGGCCAAGAAACAGACACGCCCCAAACGGTCTCGGTTTCCGCGAGGAAGGGGAAGTCCTGGGACACCCTCCACCCCCACCCCTCACCCCACACAGGGCGGGTTCAGGCGTGCCCGGCAGCCAGTAGCCTCTGGCAGATCTGACAGACGTGTGCGATAATACACACGCCCATCGAGGCCATGCCTACATAAAAGGGCACCAGGGCCCCCGGGGCAGACATTTGGCCAGCGTTTTGGGTCTCGCACCGCGCGCCCCCGATCCCATCGCGCCCGCCCTCCTCGCCGGGCGGCTCCCCGTGCGGGCCCGCGTCTCCCGCCGCTAAGGCGACGAGCAAGACAAACAACAGGCCCGCCCGACAGACCCTTCTGGGGGGGCCCATCGTCCCTAACAGGAAGATGAGTCAGTGGGGATCCGGGGCGATCCTTGTCCAGCCGGACAGCTTGGGTCGGGGGTACGATGGCGACTGGCACACGGCCGTCGCTACTCGCGGGGGCGGAGTCGTGCAACTGAACCTGGTCAACAGGCGCGCGGTGGCTTTTATGCCGAAGGTCAGCGGGGACTCCGGATGGGCCGTCGGGCGCGTCTCTCTGGACCTGCGAATGGCTATGCCGGCTGACTTTTGTGCGATTATTCACGCCCCCGCGCTATCCAGCCCAGGGCACCACGTAATACTGGGTCTTATCGACTCGGGGTACCGCGGAACCGTTATGGCCGTGGICGTAGCGCCTAAAAGGACGCGGGAATTTGCCCCCGGGACCCTGCGGGTCGACGTGACGTTCCTGGACATCCTGGCGACCCCCCCGGCCCTCACCGAGCCGATTTCCCTGCGGCAGTTCCCGCAACTGGCGCCCCCCCCTCCAACCGGGGCCGGGATACGCGCAGATCCTTGGTTGGAGGGGGCGCTCGGGGACCCAAGCGTGACTCCTGCCCTACCGGCGCGACGCCGAGGGCGGTCCCTCGTCTATGCCGGCGAGCTGACGCCGGTTCAGACGGAACACGGGGACGGCGTACGAGAAGCCATCGCCTTCCTTCCAAAACGCGAGGAGGATGCCGGTTTCGACATTGTCGTCCGTCGCCCGGTCACCGTCCCGGCAAACGGCACCACGGTCGTGCAGCCATCCCTCCGCATGCTCCACGCGGACGCCGGGCCCGCGGCCTGCTATGTGCTGGGGCGGTCGTCGCTCAACGCCCGCGGCCTCCTGGTCGTTCCTACGCGCTGGCTCCCCGGGCACGTATGTGCGTTTGTTGTTTACAACCTTACGGGGGTTCCTGTGACCCTCGAGGCCGGCGCCAAGGTCGCCCAGCTCCTGGTTGCGGGGGCGGACGCTCTTCCTTGGATCCCCCCGGACAACTTTCACGGGACCAAAGCGCTTCGAAACTACCCCAGGGGTGTTCCGGACTCAACCGCCGAACCCAGGAACCCGCCGCTCCTGGTGTTTACGAACGAGTTTGACGCGGAGGCCCCCCCGAGCGAGCGCGGGACCGGGGGTTTTGGCTCTACCGGTATTTAGCCCATAGCTTGGGGTTCGTTCCGGGCAATAAAAAACGTTTGTATCTCATCTTTCCTGTGTGTAGTTGTTTCTGTTGGATGCCTGTGGGTCTATCACACCCGCCCCTCCATCCCACAAACACAGAACACACGGGTTGGATGAAAACACGCATTTATTGACCCAAAACACACGGAGCTGCTCGAGATGGGCCAGGGCGAGGTGCGGTTGGGGAGGCTGTAGGTCTGGGAACGGACACGCGGGGACACGATTCCGGTTIGGGGTCCGGGAGGGCGTCGCCGTTTCGGGCGGCAGGCGCCAGCGTAACCTCCGGGGGCGGCGTGTGGGGGTGCCCCAAGGAGGGCGCCTCGGTCACCCCAAGCCCCCCCGAGCGGGTTCCCCCGGCAACCCCGAAGGCGGAGAGGCCAAGGGCCCGTTCGGCGATGGCCACATCCTCCATGACCACGTCGCTCTCGGCCATGCTCCGAATAGCCTGGGAGACGAGCACATCCGCGGACTIGTCAGCCGCCCCCACGGACATGTACATCTGCAGGATGGTGGCCATACACGTGTCCGCCAGGCGCCGCATCTTGTCCTGATGGGCCGCCACGGCCCCGTCGATCGTGGGGGCCTCGAGCCCGGGGTGGTGGCGCGCCAGTCGTTCTAGGTTCACCATGCAGGCGTGGTACGTGCGGGCCAAGGCGCGGGCCTTCACGAGGCGTCGGGTGTCGTCCAGGGACCCCAGGGCGTCATCGAGCGTGATGGGGGCGGGAAGTAGCGCGTTAACGACCACCAGGGCCTCCTGCAGCCGCGGCTCCGCCTCCGAGGGCGGAACGGCCGCGCGGATCATCTCATATTGTTCCTCGGGGCGCGCTCCCCAGCCACATATAGCCCCGAGAAGAGAAGCCATCGCGGGCGGGTACTGGCCCTTGGGCGCGCGGACGCAATGGGGCAGGAAGACGGGAACCGCGGGGAGAGGCGGGCGGCCGGGACTCCCGTGGAGGTGACCGCGCTTTATGCGACCGACGGGGGCGTTATTACCTCTTCGATCGCCCTCCTCACAAACTCTCTACTGGGGGCCGAGCCGGTTTATATATTCAGCTACGACGCATACACGCACGATGGCCGTGCCGACGGGCCCACGGAGCAAGACAGGTTCGAAGAGAGTCGGGCGCTCTACCAAGCGTCGGGCGGGCTAAATGGCGACTCCTTCCGAGTAACCTTTTGTTTATTGGGGACGGAAGTGGGTGGGACCCACCAGGCCCGCGGGCGAACCCGACCCATGTTCGTCTGTCGCTTCGAGCGAGCGGACGACGTCGCCGCGCTACAGGACGCCCTGGCGCACGGGACCCCGCTACAACCGGACCACATCGCCGCCACCCTGGACGCGGAGGCCACGTTCGCGCTGCATGCGAACATGATCCTGGCTCTCACCGTGGCCGTCAACAACGCCAGCCCCCGCACCGGACGCGACGCCGCCGCGGCGCAGTATGATCAGGGCGCGTCCCTACGCTCGCTCGTGGGGCGCACGTCCCTGGGACAACGCGGCCTTACCACGCTATACGTCCACCACGAGGCGCGCGTGCTGGCCGCGTACCGCAGGGCGTATTATGGAAGCGCGCAGAGTCCCTTCTGGTTTCTTAGCAAATTCGGGCCTGACGAAAAAAGCCTGGTGCTCACCACTCGGTACTACCTGCTTCAGGCCCAGCGTCTGGGGGGCGCGGGGGCCACGTACGACCTGCAGGCCATCAAGGACATCTGCGCCACCTACGCGATTCCCCACGCCCCCCGCCCCGACACCGTCAGCGCCGCGTCCCTGACCTCGTTTGCCGCCATCACGCGGTTCTGTTGCACGAGCCAGTACGCCCGCGGGGCCGCGGCGGCCGGGTTTCCGCTTTACGTGGAGCGCCGTATTGCGGCCGACGTCCGCGAGACCAGTGCGCTGGAGAAGTTCATAACCCACGATCGCAGTTGCCTGCGCGTGTCCGACCGTGAATTCATTACGTACATTTACCTGGCCCATTTTGAGTGTTTCAGCCCCCCGCGCCTAGCCACGCATCTTCGGGCCGTGACGACCCAGGACCCCAACCCCGCGGCCAACACGGAGCAGCCCTCGCCCCTGGGCAGGGAGGCCGTGGAACAATTTTTTTGCCACGTGCGCGCCCAACTGAATATCGGGGAGTACGTCAAACACAACGTGACCCCCCGGGAGACCGTCCTGGATGGCGATACGGCCAAGGCCTACCTGCGCGCTCGCACGTACGCGCCCGGGGCCCTGACGCCCGCCCCCGCGTATTGCGGGGCCGTGGACTCCGCCACCAAAATGATGGGGCGTTTGGCGGACGCCGAAAAGCTCCTGGCCCCCGCGGGTGGCCCGCGTTGGCGCCCGCCAGTCCCGGGGAGGATACGGCGGGCGGCACGCCGCCCCCACAGACCTGCGGAATCGTCAAGCGCCTCCTGAGACTGGCCGCCACGGAACAACAGGACACCACGCCCCCGGCGATCGCGGCGCTTATCCGTAATGCGGCGGTGCAGACTCCCCTGCCCGTCTACCGGATATCCATGGTCCCCACGGGACAGGCATTTGCCGCGCTGGCCTGGGACGACTGGGCCCGCATAACGCGGGACGCTCGCCTGGCCGAAGCGGTCGTGTCCGCCGAAGCGGCGGCGCACCCCGACCACGGCGCGCTGGGCAGGCGGCTCACGGATCGCATCCGCGCCCAGGGCCCCGTGATGCCCCCTGGCGGCCTGGATGCCGGGGGGCAGATGTACGTGAATCGCAACGAGATATTTAACGGCGCGCTGGCAATCACAAACATCATCCTGGATCTCGACATCGCCCTGAAGGAGCCCGTCCCCTTTCGCCGGCTCCACGAGGCCCTGGGCCACTTTAGGCGCGGGGCTCTGGCGGCGGTTCAGCTCCTGTTTCCCGCGGCCCGCGTGGACCCCGACGCATATCCCTGTTATTTTTTCAAAAGCGCATGTCGGCCCGGCCCGGCGTCCGTGGGTTCCGGCAGCGGACTCGGCAACGACGACGACGGGGACTGGTTTCCCTGCTACGACGACGCCGGTGATGAGGAGTGGGCGGAGGACCCGGGCGCCATGGACACATCCCACGATCCCCCGGACGACGAGGTTGCCTACTTTGACCIGTGCCACGAAGTCGGCCCCACGGCGGAACCTCGCGAAACGGATTCGCCCGTGTGTTCCTGCACCGACAAGATCGGACTGCGGGTGTGCATGCCCGTCCCCGCCCCGTACGTCGTCCACGGTTCTCTAACGATGCGGGGGGTGGCACGGGTCATCCAGCAGGCGGTGCTGTTGGACCGAGATTTTGTGGAGGCCATCGGGAGCTACGTAAAAAACTTCCTGTTGATCGATACGGGGGCCCGGGCGCCATGGACACATCCCACGATCCCCCGGACGACGAGGTTGCCTACTTTGACCTGTGCCACGAAGTCGGCCCCACGGCGGAACCTCGCGAAACGGATTCGCCCGTGTGTTCCTGCACCGACAAGATCGGACTGCGGGTGTGCATGCCCGTCCCCGCCCCGTACGTCGTCCACGGTTCTCTAACGATGCGGGGGGTGGCACGGGTCATCCAGCAGGCGGTGCTGTTGGACCGAGATTTTGTGGAGGCCATCGGGAGCTACGTAAAAAACTTCCTGTTGATCGATACGGGGGTGTACGCCCACGGCCACAGCCTGCGCTTGCCGTATTTTGCCAAAATCGCCCCCGACGGGCCTGCGTGCGGAAGGCTGCTGCCAGTGTTTGTGATCCCCCCCGCCTGCAAAGACGTTCCGGCGTTTGTCGCCGCGCACGCCGACCCGCGGCGCTTCCATTTTCACGCCCCGCCCACCTATCTCGCTTCCCCCCGGGAGATCCGTGTCCTGCACAGCCTGGGTGGGGACTATGTGAGCTTCTTTGAAAGGAAGGCGTCCCGCAACGCGCTGGAACACTTTGGGCGACGCGAGACCCTGACGGAGGTCCTGGGTCGGTACAACGTACAGCCGGATGCGGGGGGGACCGTCGAGGGGTTCGCATCGGAACTGCTGGGGCGGATAGTCGCGTGCATCGAAACCCACTTTCCCGAACACGCCGGCGAATATCAGGCCGTATCCGTCCGGCGGGCCGTCAGTAAGGACGACTGGGTCCTCCTACAGCTAGTCCCCGTTCGCGGTACCCTGCAGCAAAGCCTGTCGTGTCTGCGCTTTAAGCACGGCCGGGCGAGTCGCGCCACGGCGCGGACATTCGTCGCGCTGAGCGTCGGGGCCAACAACCGCCTGTGCGTGTCCTTGTGTCAGCAGTGCTTTGCCGCCAAATGCGACAGCAACCGCCTGCACACGCTGTTTACCATTGACGCCGGCACGCCATGCTCGCCGTCCGTTCCCTGCAGCACCTCTCAACCGTCGTCTTGATAACGGCGTACGGCCTCGTGCTCGTGTGGTACACCGTCTTCGGTGCCAGTCCGCTGCACCGATGTATTTACACGGTACGCCCCACCGGCACCAACAACGACACCGCCCTCGTGTGGATGAAAATGAACCAGACCCTATTGTTTCTGGGGGCCCCGACGCACCCCCCCAACGGGGGCTGGCGCAACCACGCCCATATCTGCTACGCCAATCTTATCGCGGGTAGGGTCGTGCCCTTCCAGGTCCCACCCGACGCCACGAATCGTCGGATCATGAACGTCCACGAGGCAGTTAACTGTCTGGAGACCCTATGGTACACACGGGTGCGTCTGGTGGTCGTAGGGTGGTTCCTGTATCTGGCGTTCGTCGCCCTCCACCAACGCCGATGTATGTTTGGTGTCGTGAGTCCCGCCCACAAGATGGTGGCCCCGGCCACCTACCTCTTGAACTACGCAGGCCGCATCGTATCGAGCGTGTTCCTGCAGTCCCCCTACACGAAAATTACCCGCCTGCTCTGCGAGCTGTCGGTCCAGCGGCAAAACCTGGTTCAGTTGTTTGAGACGGACCCGGTCACCTTCTTGTACCACCGCCCCGCCATCGGGGTCATCGTAGGCTGCGAGTTGATGCTACGCTTTGTGGCCGTGGGTCTCATCGTCGGCACCGCTTTCATATCCCGGGGGGCATGTGCGATCACATACCCCCTGTTTCTGACCATCACCACCTGGTGTTTTGTCTCCACCATCGGCCTGACAGAGCTGTATTGTATTCTGCGGCGGGGCCCGGCCCCCAAGAACGCAGACAAGGCCGCCGCCCCGGGGCGATCCAAGGGGCTGTCGGGCGTCTGCGGGCGCTGTTGTTCCATCATCCTGTCGGGCATCGCAATGCGATTGTGTTATATCGCCGTGGTGGCCGGGGTGGTGCTCGTGGCGCTTCACTACGAGCAGGAGATCCAGAGGCGCCTGTTTGATGTATGACGTCACATCCAGGCCGGCGGAAACCGGAACGGCATATGCAAACTGGAAACTGTCCTGTCTTGGGGCCCACCCACCCGACGCGTCATATGTAAATGAAAATCGTTCCCCCGAGGCCATGTGTAGCCTGGATCCCAACGACCCCGCCCATGGGTCCCAATTGGCCGTCCCGTTACCAAGACCAACCCAGCCAGCGTATCCACCCCCGCCCGGGTCCCCGCGGAAGCGGAACGGTGTATGTGATATGCTAATTAAATACATGCCACGTACTTATGGTGTCTGATTGGTCCTTGTCTGTGCCGGAGGTGGGGCGGGGGCCCCGCCCGGGGGGCGGAACTAGGAGGGGTTTGGGAGAGCCGGCCCCGGCACCACGGGTATAAGGACATCCACCACCCGGCCGGTGGTGGTGTGCAGCCGTGTTCCAACCACGGTCACGCTTCGGTGCCTCTCCCCGATTCGGGCCCGGTCGCTTGCTACCGGTGCGCCACCACCAGAGGCCATATCCGACACCCCAGCCCCGACGGCAGCCGACAGCCCGGTCATGGCGACTGACATTGATATGCTAATTGACCTCGGCCTGGACCTCTCCGACAGCGATCTGGACGAGGACCCCCCCGAGCCGGCGGAGAGCCGCCGCGACGACCTGGAATCGGACAGCAACGGGGAGTGTTCCTCGTCGGACGAGGACATGGAAGACCCCCACGGAGAGGACGGACCGGAGCCGATACTCGACGCCGCTCGCCCGGCGGTCCGCCCGTCTCGTCCAGAAGACCCCGGCGTACCCAGCACCCAGACGCCTCGTCCGACGGAGCGGCAGGGCCCCAACGATCCTCAACCAGCGCCCCACAGTGTGTGGTCGCGCCTCGGGGCCCGGCGACCGTCTTGCTCCCCCGAGCGGCACGGGGGCAAGGTGGCCCGCCTCCAACCCCCACCGACCAAAGCCCAGCCTGCCCGCGGCGGACGCCGTGGGCGTCGCAGGGGTCGGGGTCGCGGTGGTCCCGGGGCCGCCGATGGTTTGTCGGACCCCCGCCGGCGTGCCCCCAGAACCAATCGCAACCCGGGGGGACCCCGCCCCGGGGCGGGGTGGACGGACGGCCCCGGCGCCCCCCATGGCGAGGCGTGGCGCGGAAGTGAGCAGCCCGACCCACCCGGAGGCCCGCGGACACGGAGCGTGCGCCAAGCACCCCCCCCGCTAATGACGCTGGCGATTGCCCCCCCGCCCGCGGACCCCCGCGCCCCGGCCCCGGAGCGAAAGGCGCCCGCCGCCGACACCATCGACGCCACCACGCGGTTGGTCCTGCGCTCCATCTCCGAGCGCGCGGCGGTCGACCGCATCAGCGAGAGCTTCGGCCGCAGCGCACAGGTCATGCACGACCCCTTTGGGGGGCAGCCGTTTCCCGCCGCGAATAGCCCCTGGGCCCCGGTGCTGGCGGGCCAAGGAGGGCCCTTTGACGCCGAGACCAGACGGGTCTCCTGGGAAACCTTGGTCGCCCACGGCCCGAGCCTCTATCGCACTTTTGCCGGCAATCCTCGGGCCGCATCGACCGCCAAGGCCATGCGCGACTGCGTGCTGCGCCAAGAAAATTTCATCGAGGCGCTGGCCTCCGCCGACGAGACGCTGGCGTGGTGCAAGATGTGCATCCACCACAACCTGCCGCTGCGCCCCCAGGACCCCATTATCGGGACGGCCGCGGCGGTGCTGGATAACCTCGCCACGCGCCTGCGGCCCTTTCTCCAGTGCTACCTGAAGGCGCGAGGCCTGTGCGGCCTGGACGAACTGTGTTCGCGGCGGCGTCTGGCGGACATTAAGGACATTGCATCCTTCGTGTTTGTCATTCTGGCCAGGCTCGCCAACCGCGTCGAGCGTGGCGTCGCGGAGATCGACTACGCGACCCTTGGTGTCGGGGTCGGAGAGAAGATGCATTTCTACCTCCCCGGGGCCTGCATGGCGGGCCTGATCGAAATCCTAGACACGCACCGCCAGGAGTGTTCGAGTCGTGTCTGCGAGTTGACGGCCAGTCACATCGTCGCCCCCCCGTACGTGCACGGCAAATATTTTTATTGCAACTCCCTGTTTTAGGTACAATAAAAACAAAACATTTCAAACAAATCGCCCCACGTGTTGTCCTTCTTTGCTCATGGCCGGCGGGGCGTGGGTCACGGCAGATGGCGGGGGTGGGCCCGGCGTACGGCCTGGGTGGGCGGAGGGAACTAACCCAACGTATAAATCCGTCCCCGCTCCAAGGCCGGTGTCATAGTGCCCTTAGGAGCTTCCCGCCCGGGCGCATCCCCCCTTTTGCACTATGACAGCGACCCCCCTCACCAACCTGTTCTTACGGGCCCCGGACATAACCCACGTGGCCCCCCCTTACTGCCTCAACGCCACCTGGCAGGCCGAAACGGCCATGCACACCAGCAAAACGGACTCCGCTTGCGTGGCCGTGCGGAGTTACCTGGTCCGCGCCTCCTGTGAGACCAGCGGCACAATCCACTGCTTTTTCTTTGCGGTATACAAGGACACCCACCATACCCCTCCGCTGATTACCGAGCTCCGCAACTTTGCGGACCTGGTTAACCACCCGCCGGTCCTACGCGAACTGGAGGATAAGCGCGGGGTGCGGCTGCGGTGTGCGCGGCCGTTTAGCGTCGGGACGATTAAGGACGTCTCTGGGTCCGGCGCGTCCTCGGCGGGAGAGTACACGATAAACGGGATCGTGTACCACTGCCACTGTCGGTATCCGTTCTCAAAAACATGCTGGATGGGGGCCTCCGCGGCCCTACAGCACCTGCGCTCCATCAGCTCCAGCGGCATGGCCGCCCGCGCGGCAGAGCATCGACGCGTCAAGATTAAAATTAAGGCGTGATTTCCAACCCCCCATGAATGTGTGTAACCCCCCCCCCAAAAAAATAAAGAGCCGTAACCCAACCAAACCAGGCGTGGTGTGAGTTTGTGGACCCAAAGCCCTCAGAGACAATGCGACAGGCCAGTATGGACCGTGATACTTTTATTTATTAACTCACAGGGGCGCTTACCGCCACAGGAATACCAGAATAATGACCACCACAATCGCGACCACCCCAAATACAGCATGGCGCCACACCACGCCACAACAGCCCTGTCGCCGGTATGGGGCATGATCAGACGAGCCGCGCGCCGCGCGTTGGGCCCTGTACAGCTCGCGCGAATTGACCCTAGGAGGCCGCCACGCGCCCGAGTTTTGCGTTCGTCGCTGGTCGTCGGGCGCCAAAGCCCCGGACGGCTGTTCGGTCGAACGAACGGCCACGACAGTGGCATAGGTTGGGGGGTGGTCCGACATAGCCTCGGCGTACGTCGGGAGGCCCGACAAGAGGTCCCTTGTGATGTCGGGTGGGGCCACAAGCCTGGTTTCCGGAAGAAACAGGGGGGTTGCCAATAACCCGCCAGGGCCAAAACTCCGGCGCTGCGCACGTCGTTCGGCGCGGCGCCGGGCGCGCCGAGCGGCTCGCTGGGCGGCTTGGCGTGAGCGGCCCCGCTCCGACGCCTCGCCCTCTCCGGAGGAGGTTGGCGGAATTGGCACGGACGACAGGGGCCCAGCAGAGTACGGTGGAGGTGGGTCCGTGGGGGTGTCCAGATCAATAACGACAAACGGCCCCTCGTTCCTACCAGACAAGCTATCGTAGGGGGGCGGGGGATCAGCAAACGCGTTCCCCGCGCTCCATAGACCCGCGTCGGGTTGCGCCGCCTCCGAAGCCATGGATGCGCCCCAAAGCCACGACTCCCGCGCGCTAGGTCCTTGGGGTAAGGGAAAAGGCCCTACTCCCCATCCAAGCCAGCCAAGTTAACGGGCTACGCCTTCGGGGATGGGACTGGCACCCCGGCGGATTTTGTTGGGCTGGTACGCGTCGCCCAACCGAGGGCCGCGTCCACGGGACGCGCCTTTTATAACCCCGGGGTCATTCCCAACGATCACATGCAATCTAACTGGCTCCCCTCTCCCCTCTCCCCCCCTCTCCCCAGCAGGAGCGGGGTGTTGCGCCGGGGGACGTCTGGAGGAGCGGGAGGTGCGCGGGACGGTGGATGAGGAACAGGAGTTGTTGCGCGGTGAGTTGTCGCTGTGAGTTGTGTTGTTGGGCAGGTGTGGTGGATGACGTGACGTGTGACGTGCGGATTGCGCCGTGCTTTGTTGGTGTTGTTTTACCTGTGGCAGCCCGGGCCCCCCGCGGGCGCGCGCGCGCGCAAAAAAGGCGGGCGGCGGCCCCCGCTCCTCCCCCGCCCCTCCCCCGCTCCTCCCCCGCTCCCCCCCGCCCCCGGCCCCGCCCCCACCCCCCCCGCGCGCGCACGCCGCCCGGACCGCCGCCCGCCCTTTTTGCGCCCGCGCGCGCCCGCGGGGGGCCCTGGCTGCCACAGGTAAAACAACACCAACAAAGCACGGCGCAATCCGCACGTCACACGTCACGTCATCCACCACCCTGCCCAACAACACAACTCACAGCGACAACTCCCGCGCAACAACTCCTGTTCCTCATCCACACGTCACCGCGCCCCTCCCGCTCCTCCAGACGTACCCCGGCGCAACACCCGCTCCTGCTACACCCCACCGCCCCTCCCCAGCCCCAGCCCTCCCCAGCCCCAGCCCTCCCCCGGGAGGGGGCGAGGGGCGGGAGGGGGCGAGGGGCGGGAGGGGGCGAGGGGCGGTGGTGGGGCGCGGGCGCCCCCGGAGGGTTGGATCTCTGACCTGAGATTGGCGGCACTGAGGAGAGATGCCCGAACCCCCCCGAGGGAGCGCGGGACGCGGTGGGGAGGGCTGGGGCTGGGGAGGGCGGGGCGGGGGGGCGGGGCGGGGGGGGGGGGGGGGGGGGGCGGGGGCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCGCCCCCCCCCGCCCCCCGCCCCCCCCCGCCCCTCGCCCCCTCCCGCCCCTCGCCCCCTCCCGCCCCTCGAATAAACAACGCTACTGCAAAACTTAATCAGGTCGTTGCCGTTTATTGCGTCTTCGGGTTTCACAAGCGCCCCGCCCCGTCCCGGCCCGTTACAGCACCCCGTCCCCCTCGAACGCGCCGCCGCGTCTTCGTCCCAGGCGCCTTCCCAGTCCACAACGTCCCGTCGCGGGGGCGTGGCCAAGCCCGCCTCCGCCCCCAGCACCTCCACGGCCCCCGCCGCCGCCAGCACGGTGCCGCTGCGGCCCGTGGCCGAGGCCCAGCGAATCCCGGGCGGCGCCGGCGGCAGGGCCCCCGGGCCGTCGTCGTCGTCGCCGCGCAGCACCAGCGGGGGGGCGTCGTCGTCGGGCTCCAGCAGGGCGCGGGCGCAAAAGTCCCTCCGCGGCCCGCGCCACCGGGCCGGGCCGGCGCGCACCGCCTCGCGCCCCAGCGCCACGTACACGGGCCGCAGCGGCGCGCCCAGGCCCCAGCGCGCGCAGGCGCGGTGCGAGTGGGCCTCCTCCTCGCAGAAGTCCGGCGCGCCGGGCGCCATGGCGTCGGTGGTCCCCGAGGCCGCCGCCCGGCCGTCCAGCGCCGGCAGCACGGCCCGGCGGTACTCGCGCGGGGACATGGGCACCGGCGTGTCCGGGCCGAGCGCGTGCGCACGCGGTAGCGCCGTTGCCGCCGCGGCACGGCGCAGCGGCGGCGCGTCGGGGTACAGGCGCGCGTGCGCGGCCTCCACGCGCGCGAAGACCCCCGGGCCGAACACGCGGCCCGAGGCCAGCACCGTGCGGCGCAGGTCCCGCGCCGCCGGCCAGCGCACGGCGCACTGCACGGCGGGCAGCAGGTCGCACGCCAGGTAGGCGTGCTGCCGCGACACCGCGGGCCCGTCGGCGGGCCAGTCGCAGGCGCGCACGGTGTTGACCACGATGAGCCGCCGGTCGCCGGCGCTGGCGAGCAGCCCCAGAAACTCCACGGCCCCGGCGAAGGCCAGGTCCCGCGTGGACAGCAGCAGCACGCCCTGCGCGCCCAGCGCCGACACGTCGGGGGCGCCGGTCCAGTTGCCCGCCCAGGCGGCCGTGTCCGGCCCGCACAGCCGGTTGGCCAGGGCCGCCAGCAGGCAGGACAGCCCGCCGCGCTCGGCGGACCACTCCGGCGGCCCCCCCGAGGCCCCGCCGCCGGCCAGGTCCTCGCCCGGCAGCGGCGAGTACAGCACCACCACGCGCACGTCCTCGGGGTCGGGGATCTGGCGCATCCAGGCCGCCAGGCGGCGCAGCGGGCCCGAGGCGCGCGGGGGGCCAAAGAGGCGGCCCCCGGCGGCCCCGTGGGGGTGGGGGCCCCCACCCCCACGGGGCCGCCGGGGGCCGCCTCTTTGGCCCCCTGCGCGCCTCGGGCCCGCTGCGCCGCATGGCGGCCTGGATGCGCCAGATCCCCGACCCCGAGGACGTGCGCGTGGTGGTGCTGTACTCGCCGCTGCCGGGCGAGGACCTGGCCGGCGGCGGGGCCTCGGGGGGGCCGCCGGAGTGGTCCGCCGAGCGCGGCGGGCTGTCCTGCCTGCTGGCGGCCCTGGCCAACCGGCTGTGCGGGCCGGACACGGCCGCCTGGGCGGGCAACTGGACCGGCGCCCCCGACGTGTCGGCGCTGGGCGCGCAGGGCGTGCTGCTGCTGTCCACGCGGGACCTGGCCTTCGCCGGGGCCGTGGAGTTTCTGGGGCTGCTCGCCAGCGCCGGCGACCGGCGGCTCATCGTGGCAACACCGTGCGCGCCTGCGACTGGCCCGCCGACGGGCCCGCGGTGTCGCGGCAGCACGCCTACCTGGCGTGCGACCTGCTGCCCGCCGTGCAGTGCGCCGTGCGCTGGCCGGCGGCGCGGGACCTGCGCCGCACGGTGCTGGCCTCGGGCCGCGTGTTCGGCCCGGGGGTCTTCGCGCGCGTGGAGGCCGCGCACGCGCGCCTGTACCCCGACGCGCCGCCGCTGCGCCTGTGCCGCGGCGGCAACGTGCGCTACCGCGTGCGCACGCGCTTCGGCCCGGACACGCCGGTGCCCATGTCCCCGCGCGAGTACCGCCGGGCCGTGCTGCCGGCGCTGGACGGCCGGGCGGCGGCCTCGGGGACCACCGACGCCATGGCGCCCGGCGCGCCGGACTTCTGCGAGGAGGAGGCCCACTCGCACCGCGCCTGCGCGCGCTGGGGCCTGGGCGCGCCGCTGCGGCCCGTGTACGTGGCGCTGGGGCGCGAGGCGGTGCGCGCCGGCCCGGCCCGGTGGCGCGGGCCGCGGAGGGACTTTTGCGCCCGCGCCCTGCTGGAGCCCGACGACGACGCCCCCCCGCTGGTGCTGCGCGGCGACGACGACGACGGCCCGGGGGCCCTGCCGCCGGCGCCGCCCGGGATTCGCTGGGCCTCGGCCACGGGCCGCAGCGGCACCGTGCTGGCGGCGGCGGGGGCCGTGGAGGTGCTGGGGGCGGAGGCGGGCTGGCCACGCCCCCGCGCGGGACGTTGTGGACTGGGAAGGCGCCTGGGCGAAGACGCGGCGGCGCGTCGAGGGGGACGGGGTGCTGTACGGGCCGGGACGGGGCGGGGCGCTTGTGAAACCCGAAGACGCAATAAACGGCAACGACCTGATTAAGTTTTGCAGTAGCGTTGTTTATTCGAGGGGCGGGAGGGGGCGAGGGGCGGCCGGCCCGCACAGCCGGTTGGCCAGGGCCGCCAGCAGGCAGGACAGCCCGCCGCGCTCGGCGGACCACTCCGGCGGCCCCCCCGAGGCCCCGCCGCCGGCCAGGTCCTCGCCCGGCAGCGGCGAGTACAGCACCACCACGCGCACGTCCTCGGGGTCGGGGATCTGGCGCATCCAGGCCGCCATGCGGCGCAGCGGGCCCGAGGCGCGCAGGGGGCCAAAGAGGCGGCCCCCGGCGGCCCCGTGGGGGTGGGGGTTCTCGTCGTCGTCGCCGCCGCACGCGGCCTGGGCGGCGGGGGCGGGCCCGGCGCACCGCGCGGCGATCGAGGCCAGGGCCCGCGGGTCAAACATGAGGGCCGGTCGCCAGGGGACGGGGAACAGCGGGTGGTCCGTGAGCTCGGCCACGGCGCGCGGGGAGCAGTAGGCCTCCAGGGCGGCGGCCGCGGGCGCCGCCGTGTGGCTGGGCCCCCGGGGCTGCCGCCGCCAGCCGCCCAGGGGGTCGGGGCCCTCGGCGGGCCGGCGCGACAGCGCCAGGGGGCGCGGGCGGGCCTGCGCCGCGGCGCCCGGGCCGCCGCGGGCTGGGCGGGGGTGGGCTCGGGCCCGGGGGCGTGGAGGGGGGCGCGGGGAGGGGGGCGCGGGCGTCCGAGCCGGGGGCGTCCGCGCCGCTCTTCTTCGTCTTCGGGGGTCGCGGGCCGCCGCCTCCGGGCGGCCGGGCCGGGCCGGGACTCTTGCGCTTGCGCCCCTCCCGCGGCGCGGCGGAGGCGGCGGCGGCCGCCAGCGCGTCGGCGGCGTCCGGTGCGCTGGCCGCCGCCGCCAGCAGGGGGCGGAGGCTCTGGTTCTCAAACAGCAGGTCCGCGGCGGCGGCGGCCGCGGAGCTCGGCAGGCGCGGGTCCCGCGGCAGCGCGGGGCCCAGGGCCCCGGCGACCAGGCTCACGGCGCGCACGGCGGCCACGGCGGCCTCGCTGCCGCCGGCCACGCGCAGGTCCCCGCGCAGGCGCATGAGCACCAGCGCGTCGCGCACGAACCGCAGCTCGCGCAGCCACGCGCGCAGGCGGGGCGCGTCGGCGTGCGGCGGCGGCGGGGAAGCGGGGCCCGCGGGTCCCTCTGGCCGCGGGGGGCTGGCGGGCCGGGCCCCGGCCAGCCCCGGGACGGCCGCCAGGTCGCCGTCGAAGCCCTCGGCCAGCGCCTCCAGGATCCCGCGGCAGGCGGCCAGGCACTCGACGGCCACGCGGCCGGCCTGGGCGCGGCGCCCGGCGTCGGCGTCGGCGTGGCGGGCGGCGTCGGGGTCGTCGCCCCCCACGGGGGAGGCGGGCGCGGCGGACAGCCGCCCCAGGGCGGCGAGGATCCCCGCGGCGCCGTACCCGGCGGGCACCGCGCGCTCGCCCGGTGCGGCGGCGGCGACGGCGGCGACCCCCTCGTCATCTGCGCCGGCGCCGGGGCTCCCCGCGGCCCCCGTCAGCGCCGCGTTCTCGCGCGCCAACAGGGGCGCGTAGGCGCGGCGCAGGCTGGTCAGCAGGAAGCCCTTCTGCGCGCGGTCGTATCGGCGGCTCATGGCCACGGCGGCCGCCGCGTGCGCCAGGCCCCGCCGAAGCGGCCGGCCGCCATGGCGTAGCCCAGGTGGGGCACGGCCCGCGCCACGCTGCCGGTGATGAAGGAGCTGCTGTTGCGCGCGGCGCCCGAGATCCGGAAGCAGGCCTGGTCCAGCGCCACGTCCCCGGGGACCACGCGCGGGTTCTGGAGCCACCCCATGGCCTCCGCGTCCGGGGGCCTGCGCGGGGACCTGCGCGTGGCCGGCGGCAGCGGGCCGCCGTGGCCGCCGGCGCGCCGTGGCCGGTCGCCGGGGCCCTGGGCCCCGCGCTGCCGCGGGACCCGCGCCTGCCGAGCTCCGCGGCCGCCGCCGCCGCGGACCTGCTGTTTGAGAACCAGAGCCTCCGCCCCCTGCTGGCGGCGGCGGCCAGCGCACCGGACGCCGCCGACGCGCTGGCGGCCGCCGCCGCCTCCGCCGCGCCGCGGGAGGGGCGCAAGCGCAAGAGTCCCGGCCCGGCCCGGCCGCCCGGAGGCGGCGGCCCGCGACCCCCGAAGACGAAGAAGAGCGGCGCGGACGCCCCCGGCTCGGCGCCCGCGCCCCCCTCCCCGCGCCCCCCTCCACGCCCCCGGGCCCAGCCCACCCCCCCCCACCCGCGGCGGCCCGGGGCGCCGCGGCGCAGGCCCGCCCCCGCCCCTGGCGCTGTCGCGCCGGCCCCCCGAGGGCCCCGACCCCCGGGCGGCTGGCGGCGGCAGCCCCGGGGGCCCAGCCACACGGCGGCGCCCGCGGCCGCCGCCCTGGAGGCCTACTGCTCCCCGCGCGCCGTGGCCGAGCTCACGGACCACCCGCTGTTCCCCGTCCCCTGGCGACCGGCCCTCATGTTTGACCCGCGGGCCCTGGCCTCGATCGCCGCGCGGTGCGCCGGGCCCGCCCCCGCCGCCCAGGCCGCGTGCGGCGGCGACGACGACGAGAACCCCCGGGGGGGGGGGGGGGGGGGGGGGGGGGGGTGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGTGGGTGGGGAGTGGCAAGGAAGAAACAAGCCCGACCACCAGACAGAAAATGTAACCATACCCAAACCGACTCTGGGGGCTGTTTGTGGGGTCGGAACCATAGGATGAACAAACCACCCCGTACCTCCCGCACCCAAGGGTGCGGGTGGCTCATCGGCATCTGTCCGGTATGGGTTGTTCCCCACCCACTCGCGTTCGGACGTCTTAGAATCATGGCGGTTTTCTATGCCGACATCGGTTTTTCCCCCGCAATAAACACGATGCGATAAAAACTGTTTGTAAAATTTATTAAGGGGACAAAATGCCCTAGCACAGGGGTGGGGTTAGGGCCGGGTCCCCACACCCAAACGCACCAAACAGATGCAGGCAGTGGGTCGAGTACAGCCCCGCGTACGAACACGTCGATGCGTGTGTCAGACAGCACCAGAAAGCACAGGCCATCAACAGGTCGTGCATGTGTCGGTGGGTTTGGACGCGGGGGGCCATGGTGGTGATAAAGTTAATGGCCGCCGTCCGCCAGGGCCACAGGGGCGACGTCTCTTGGTTGGCCCGGAGCCACTGGGTGTGGACCAGCCGCGCGTGGCGGCCCAACATGGCCCCTGTAGCCGGGGGCGGGGGATCGCGCACGTTTGCAGCGCACATGCGAGACACCTCGACCACGGTTCGAAAGAAGGCCCGGTGGTCCGCGGGCAACATCACCAGGTGCGCAAGCGCCCGGGCGTCCAGAGGGTAGAGCCCTGAGTCATCCGAGGTTGGCTCATCGCCCGGGTCTTGCCGCAAGTGCGTGTGGGTTGGGCTTCCGGTGGGCGGGACGCGAACCGCGGTGTGGATCCCGACGCGGGCCCGAGCGTATGCTCCATCTTGTGGGGAGAAGGGGTCTGGGCTCGCCAGGGGGGCATACTTGCCCGGGCTATACAGACCCGCGAGCCGTACGTGGTTCGCGGGGGGTGCGTGGGGTCCGGGGCTCCCTGGGAGACCGGGGTTGTCGTGGATCCCTGGGGTCACGCGGTACCCTGGGGTCTCTGGGAGCTCGCGGTACTCTGGGTTCCCTAGGTTCTCGGGGTGGTCGCGGAACCCGGGGCTCCCGGGGAACACGCGGTGTCCTGGGGATTGTTGGCGGTCGGACGGCTTCAGATGGCTTCGAGATCGTAGTGTCCGCACCGACTCGTAGTAGACCCGAATCTCCACATTGCCCCGCCGCTTGATCATTATCACCCCGTTGCGGGGGTCCGGAGATCATGCGCGGGTGTCCTCGAGGTGCGTGAACACCTCTGGGGTGCATGCCGGCGGACGGCACGCCTTTTAAGTAAACATCTGGGTCGCCCGGCCCAACTGGGGCCGGGGGTTGGGTCTGGCTCATCTCGAGAGACACGGGGGGGAACCACCCTCCGCCCAGAGACTCGGGTGATGGTCGTACCCGGGACTCAACGGGTTACCGGATTACGGGGACTGTCGGTCACGGTCCCGCCGGTTCTTCGATGTGCCACACCCAAGGATGCGTTGGGGGCGATTTCGGGCAGCAGCCCGGGAGAGCGCAGCAGGGGACGCTCCGGGTCGTGCACGGCGGTTCTGGCCGCCTCCCGGTCCTCACGCCCCCTTTTATTGATCTCATCGCGTACGTCGGCGTACGTCCTGGGCCCAACCCGCATGTTGTCCAGGAAGGTGTCCGCCATTTCCAGGGCCCACGACATGCTTTTCCCGACGAGCAGGAAGCGGTCCACGCAACGGTCGCCGCCGGTCGCCTCGACGAGGGCGTTCCTCCTGCGGGAAGGCACGAACGCGGGTGAGCCCCCGCGTCCCCCCTCCTCCGCCCCCGCGTCCCCCCTCCTCCGCCCCCGCGTCCCCCCTCCTCCGCCCCCGCGTCCCCCCTCCTCCGCCCCCGCGTCCCCCCTCCTCCGCCCCCGCGTCCCCCCTCCTCCGCCCACCCAAGGTGCTTACCCGTGCAAAAAAGGCGGACCGGTGGGTTTCTGTCGTCGGAGGCCCCCGGGGTGCGTCCCCTGTGTTTCGTGGGTGGGGTGGGCGGGTCTTTCCCCCCCGCGTCCGCGTGTCCCTTTCCGATGCGATCCCGATCCCGAGCCGGGGCGTCGCGATGCCGACGCCGTCCGCTCCGACGGCCCTCTGCGACTCCCGCTCCCGGTCCGCGTGCTCCGCAGCCGCTCCCGTCGTTCGTGGCCGGCGCCGTCTGCGGGCGTCGGTCGCGCCGGGCCTTTATGTGCGCCGGAGAGACCCGCCCCCCGCCGCCCGGGTCCGCCCCCGGGGCCGGCGCGGAGTCGGGCACGGCGCCAGTGCTCGCACTTCGCCCTAATAATATATATATATTGGGACGAAGTGCGAACGCTTCGCGTTCTCACTTCTTTTACCCGGCGGCCCCGCCCCCTTGGGGCGGTCCCGCCCGCCGGCCAATGGGGGGGCGGCAAGGCGGGCGGCCCAAGGGCCGCCCGCCGTCCCGTGGTCCCGGCGTCCGGCGGGCGGGACCGGGGGCCCGGGGACGGCCAACGGGCGCGCGGGGCTCGTATCTCATTACCGCCGAACCGGGAAGTCGGGGCCCGGGCCCCGCCCCCTGCCCGTTCCTCGTTAGCATGCGGAACGGAAGCGGAAACCGCCGGATCGGGCGGTAATGAGATGCCATGCGGGGCGGGGCGCGGACCCACCCGCCCTCGCGCCCCGTCCATGGCAGATGGCGCGGATGGGCGGGGCCGGGGGTTCGACCAACGGGCCGCGGCCACGGGCCCCCGGCGTGCCGGCGTCGGGGCGGGGTCGTGCATAATGGAATTCCGTTCGGGGTGGGCCCGCCGGGGGGCGGGGGGCCGGCGGCCTCCGCTGCTCCTCCTTCCCGCCGGCCCCTGGGACTATATGAGCCCGAGGACGCCCCGATCGTCCACACGGAGCGCGGCTGCCGACACGGATCCACGACCCGACGCGGGACCGCCAGAGACAGACCGTCAGACGCTCGCCGCGCCGGGACGCCGATACGCGGACGAAGCGCGGGAGGGGGATCGGCCGTCCCTGTCCTTTTTCCCCACCCAAGCATCGACCGGTCCGCGCTAGTTCCGCGTCGACGGCGGGGGTCGTCGGGGTCCGTGGGTCTCGCCCCCTCCCCCCATCGAGAGTCCGTAGGTGACCTACCGTGCTACGTCCGCCGTCGCAGCCGTATCCCCGGAGGATCGCCCCGCATCGGCGATGGCGTCGGAGAACAAGCAGCGCCCCGGCTCCCCGGGCCCCACCGACGGGCCGCCGCCCACCCCGAGCCCAGACCGCGACGAGCGGGGGGCCCTCGGGTGGGGCGCGGAGACGGAGGAGGGCGGGGACGACCCCGACCACGACCCCGACCACCCCCACGACCTCGACGACGCCCGGCGGGACGGGAGGGCCCCCGCGGCGGGCACCGACGCCGGCGAGGACGCCGGGGACGCCGTCTCGCCGCGACAGCTGGCTCTGCTGGCCTCCATGGTAGAGGAGGCCGTCCGGACGATCCCGACGCCCGACCCCGCGGCCTCGCCGCCCCGGACCCCCGCCTTTCTAGCCGACGACGATGACGGGGACGAGTACGACGACGCAGCCGACGCCGCCGGCGACCGGGCCCCGGCCCGGGGCCGCGAACGGGAGGCCCCGCTACGCGGCGCGTATCCGGACCCCACGGACCGCCGTCGCCGCGCCCGCCGGCCCAGCCGCCGCGGAGACGTCGTCACGGCCGGCGGCGGCCATCGGCGTCATCGACCTCGTCGGACTCCGGGTCCTCGTCCTCGTCGTCCGCATCCTCTTCGTCCTCGTCGTCCGACGAGGACGAGGACGACGACGGCAACGACGCGGCCGACCACGCACGCGAGGCGCGGGCCGTCGGGCGGGGTCCGTCGAGCGCGGCGCCGGAAGCCCCCGGGCGGACGCCGCCCCCGCCCGGGCCACCCCCCCTCTCCGAGGCCGCGCCCAAGCCCCGGGCGGCGGCGAGGACCCCCGCGGCCTCCGCGGGCCGCATCGAGCGCCGCCGGGCCCGCGCGGCGGTGGCCGGCCGCGACGCCACGGGCCGCTTCACGGCCGGGCAGCCCCGGCGGGTCGAGCTGGCGCCGACGCGGCCTCCGGCGCCTTCTCGCGCGCTACGCGACGGGTCGTCGCGGGGAGCCGTGGCCCGGCGCCGGGCCCCCGCCCCCGGGGCGGGTGCTGTACGGCGGCCTGGGCGACAGCCGCCCGGGCCTCTGGGGGGCGCCCGAGGCGGAGGAGGCGCGACGCCGGTTCGAGGCCTCGGGCGCCCCGGCGGCCGTGTGGGCGCCCGAGCTGGGCGACGCCGCGCAGCAGTACGCCCTGATCACGCGGCTGCTGTACACCCCGGACGCGGAGGCCATGGGGTGGCTCCAGAACCCGCGCGTGGTCCCCGGGGACGTGGCGCTGGACCAGGCCTGCTTCCGGATCTCGGGCGCCGCGCGCAACAGCAGCTCCTTCATCACCGGCAGCGTGGCGCGGGCCGTGCCCCACCTGGGCTACGCCATGGCGGCCGGCCGCTTCGGCTGGGGCCTGGCGCACGCGGCGGCCGCCGTGGCCATGAGCCGCCGATACGACCGCGCGCAGAAGGGCTTCCTGCTGACCAGCCTGCGCCGCGCCTACGCGCCCCTGTTGGCGCGCGAGAACGCGGCGCTGACGGGGGCCGCGGGGAGCCCCGGCGCCGGCGCAGATGACGAGGGGGTCGCCGCCGTCGCCGCCGCCGCACCGGGCGAGCGCGCGGTGCCCGCCGGGTACGGCGCCGCGGGGATCCTCGCCGCCCTGGGGCGGCTGTCCGCCGCGCCCGCCTCCCCCGTGGGGGGCGACGGGGCGTACAGCAGCCGCGTGATCAGGGCGTACTGCTGCGCGGCGTCGCCCGCTCGGGCGCCCACACGGCCGCCGGGGCGCCCGAGGCCTCGACCCGGCGTCGCGCCTCCTCCGCCTCGGGCGCCCCCCAGAGGCCCGGGCGGCTGTCGCCCAGGCCGCCGTACAGCACCCGCCCCGGGGGCGGGGGCCCGGCGCCGGGCCACGGCTCCCCGCTGACGACCCGTCGCGATAGCGCGCGTAGAAGGCGCCGGAGGCCGCGTCGGCGTCCAGCTCGACCCGCCGGGGCTGCCCGGCCGTGAAGCGGCCCGTGGCGTCGCGGCCGGCCACCGCCGCGCGGGCCCGGCGGCGCTCGATGCGGCCCGCGGAGGCCGCGGGGGTCCTCGCCGCCGCCCGGGGCTTGGGCGCGGCCTCGGAGAGGGGGGGTGGCCCGGGCGGGGGCGGCGTCCGCCCGGGGGCTTCCGGCGCCGCGCTCGACGGACCCCGCCCGACGGCCCGCGCCTCGCGTGCGTGGTCGGCCGCGTCGTTGCCGTCGTCGTCCTCGTCCTCGTCGGACGACGAGGACGAAGAGGATGCGGACGACGAGGACGAGGACCCGGAGTCCGACGAGGTCGATGACGCCGATGGCCGCCGCCGGCCGTGACGACGTCTCCGCGGCGGCTGGGCCGGCGGGCGCGGCGACAGGCGGTCCGTGGGGGCCGGATACGCGCCGCGCCGCCCGGGGGCTTCCGGCGCCGCGCTCGACGGACCCCGCCCGACGGCCCGCGCCTCGCGTGCGTGGTCGGCCGCGTCGTTGCCGTCGTCGTCCTCGTCCTCGTCGGACGACGAGGACGAAGAGGATGCGGACGACGAGGACGAGGACCCGGAGTCCGACGAGGTCGATGACGCCGATGGCCGCCGCCGGCCGTGACGACGTCTCCGCGGCGGCTGGGCCGGCGGGCGCGGCGACAGGCGGTCCGTGGGGTCCGGATACGCGCCGCGTAGCGGGGCCTCCCGTTCGCGGCCCCGGGCCGGGGCCCGGTCGCCGGCGGCGTCGGCTGCGTCGTCGTACTCGTCCCCGTCATCGTCGTCGGCTAGAAAGGCGGGGGTCCGGGGCGGCGAGGCCGCGGGGTCGGGCGTCGGGATCGTCCGGACGGCCTCCTCTACCATGGAGGCCAGCAGAGCCAGCTGTCGCGGCGAGACGGCGTCCCCGGCGTCCTCGCCGGCGTCGGTGCCCGCCGCGGGGGCCCTCCCGTCCCGCCGGGCGTCGTCGAGGTCGTGGGGGTGGTCGGGGTCGTGGTCGGGGTCGTCCCCGCCCTCCTCCGTCTCCGCGCCCCACCCGAGGGCCCCCCGCTCGTCGCGGTCTGGGCTCGGGGTGGGCGGCGGCCCGTCGGTGGGGCCCGGGGAGCCGGGGCGCTGCTTGTTCTCCGACGCCATCGCCGATGCGGGGCGATCCTCCCCCGACGACCCCCGCCGTCGACGCGGAACTAGCGCGGACCGGTCGATGCTTGGGTGGGGAAAAAGGACAGGGACGGCCGATCCCCCTCCCGCGCTTCGTCCGCGTATCGGCGTCCCGGCGCGGCGAGCGTCTGACGGTCTGTCTCTGGCGGTCCCGCGTCGGGTCGTGGATCCGTGTCGGCAGCCGCGCTCCGTGTGGACGATCGGGGCGTCCTCGGGCTCATATAGTCCCGGGGCCGGCGGGAGGGAGGAGCAGCGGAGGCCGCCGGCCCCCCGCCCCCCGGCGGGCCCGACCCCGCCCCGACGCCGGCACGCCGGGGGCCCGTGGCCGCGGCCCGTTGGTCGAACCCCCGGCCCCGCCCATCCGCGCCATCTGCCATGGACGGGGCGCGAGGGCGGGTGGGTCCGCGCCCCGCCCCGCATGGCATCTCATTACCGCCCGATCCGGCGGTTTCCGCTTCCGTTCCGCATGCTAACGAGGAACGGGCAGGGGGCGGGGCCCGGGCCCCGACTTCCCGGTTCGGCGGTAATGAGATACGAGCCCCGCGCGCCCGTTGGCCGTCCCCGGGCCCCCGTCCCGCCCGCCGGACGCCGGGACCACGGGACGCGGAGCGGACGGCGTCGGCATCGCGACGCCCCGGCTCGGGATCGGGATCGCATCGGAAAGGGACACGCGGACGCGGGGGGGAAAGACCCGCCCACCCCACCCACGAAACACAGGGGACGCCCCCGGGGGCCCCGACGACAGAAACCCCCGGTCCGCCTTTTTTGCACGGGTAAGCGCCTTGGGTGGGCGGAGGAGGGGGGACGCGGGGGCGGAGGAGGGGGGACGCGGGGGCGGAGGAGGGGGGAGCGGGGGGGAGGAGGGGGGACGCGGGGGCGGAGGAGGGGGGACGCGGGGGCGGAGGAGGGGGGGGGGGGGGGAGCCACTGTGGTCCTCCGGGCGTTTTCTGGATGGCCGACATTTCCCCAGGCGCTTTTGTGCCTTGTGTAAAAGCGCGGCGTCCCGCTCTCCGATCCCCGCCCCTGGGCACGCGCAAGCGCAAGCGCCCTGCCCGCCCCCTCTCATCGGAGTCTGAGGTCGAATCCGAGACAGCCTTGGAGTCTGAGGTCGAATCCGAGACAGCATCGGATTCGACCGAGTCTGGGGACCAGGAGGAAGCCCCCCGCATCGGTGGCCGTAGGGCCCCCCGGAGGCTTGGGGGGCGGTTTTTTCTGGACATGTCGGCGGAATCCACCACGGGGACGGAAACGGATGCGTCGGTGTCGGACGACCCCGACGACACGTCCGACTGGTCTTGTGACGACATTCCCCCACGACCCAAGCGGGCCCGGGTAAACCTGCGGCTCACTAGCTCTCCCGATCGGCGGGATGGGGTTATTTTTCCTAAGATGGGGCGGGTCCGGTCTACCCGGGAAACGCAGCCCCGGGCCCCCACCCCGTCGGCCCCAAGCCCAAATGCAATGCTCCGGCGCTCGGTGCGCCAGGCCCAGAGGCGGAGCAGCGCACGATGGACCCCCGACCTGGGCTACATGCGCCAGTGTATCAATCAGCTGTTTCGGGTCCTGCGGGTCGCCCGGGACCCCCACGGCAGTGCCAACCGCCTGCGCCACCTGATACGCGACTGTTACCTGATGGGATACTGCCGAGCCCGTCTGGCCCCGCGCACGTGGTGCCGCTTGCTGCAGGTGTCCGGCGGAACCTGGGGCATGCACCTGCGCAACACCATACGGGAGGTGGAGGCTCGATTCGACGCCACCGCAGAACCCGTGTGCAAGCTTCCTTGTTTGGAGGCCAGACGGTACGGCCCGGAGTGTGATCTTAGTAATCTCGAGATTCATCTCAGCGCGACAAGCGATGATGAAATCTCCGATGCCACCGATCTGGAGGCCGCCGGTTCGGACCACACGCTCGCGTCCCAGTCCGACACGGAGGATGCCCCCTCCCCCGTTACGCTGGAAACCCCAGAACCCCGCGGGTCCCTCGCTGTGCGTCTGGAGGATGAGTTTGGGGAGTTTGACTGGACCCCCCAGGAGGGCTCCCAGCCCTGGCTGTCTGCGGTCGTGGCCGATACCAGCTCCGTGGAACGCCCGGGCCCATCCGATTCTGGGGCGGGTCGCGCAGCAGAAGACCGCAAGTGTCTGGACGGCTGCCGGAAAATGCGCTTCTCCACCGCCTGCCCCTATCCGTGCAGCGACACGTTTCTCCGGCCGTGAGTCCGGICGCCCCGACCCCCTTGTATGTCCCCAAAATAAAAGACCAAAATCAAAGCGTTTGTCCCAGCGTCTTAATGGCGGGAAGGGGGAGAGAAACAGACCACGCGTACATGGGGGGTGTTTGGGGGTTTATTGACATCGGGGCTACAGGGTGGTAACCGGATAGCAGATGTGAGGAAGTCTGGGCCGTTCGCCGCGAACGGCGATCAGAGGGTCCGTTTCTTGCGGACCACGGCCCGGTGATGTGGGTTGCTCGTCTAAAATCTCGGGCATACCCATACACGCACAACACGGACGCCGCACCGAATGGGACGTCGTAAGGGGGTGGGAGGTAGCTGGGTGGGGTTTGTGCAGAGCAATCAGGGACCGCAGCCAGCGCATACAATCGCGCTCCCGTCCGTTGGTCCCGGGCAGGACCACGCCGTACTGGTATTCGTACCGGCTGAGCAGGGTCTCCAGGGGGTGGTTGGGTGCCGCGGGGAACGGGGTCCACGCCACGGTCCACTCGGGCAAAAACCGAGTCGGCACGGCCCACGGTTCTCCCACCCACGCGTCTGGGGTCTTGATGGCGATAAATCTTACCCCGAGCCGGATTTTTTGGGCGTATTCGAGAAACGGCACACACAGATCCGCCGCGCCTACCACCCACAAGTGGTAGAGGCGAGGGGGGCTGGGTTGGTCTCGGTGCAACAGTCGGAAGCACGCCACGGCGTCCACGACCTCGGTGCTCTCCAAGGGGCTGTCCTCCGCAAACAGGCCCGTGGTGGTGTTTGGGGGGCAGCGACAGGACCTAGTGCGCACGATCGGGCGGGTGGGTTTGGGTAAGTCCATCAGCGGCTCGGCCAACCGTCGAAGGTTGGCCGGGCGAACGACGACCGGGGTACCCAGGGGTTCTGATGCCAAAATGCGGCACTGCCTAAGCAGGAAGCTCCACAGGGCCGGGCTTGCGTCGACGGAAGTCCGGGGCAGGGCGTTGTTCTGGTCAAGGAGGGTCATTACGTTGACGACAACAACGCCCATGTTGGTATATTACAGGCCCGTGTCCGGTTTGGGGCACTTGCAGATTTGTAAGGCCACGCACGGCGGGGAGACAGGCCGACGCGGGGGCTGCTCTAAAAATTTAAGGGCCCTACGGTCCACAGACCCGCCTTCCCGGGGGGGCCCTTGGAGCGACCGGCAGCGGAGGCGTCCGGGGGAGGGGAGGGTTATTTACGGGGGGGTAGGTCAGGGGGTGGGTCGTCAAACTGCCGCTCCTTAAAACCCCGGGGCCCGTCGTTCGGGGTGCTCGTTGGTTGGCACTCACGGTGCGGCGAATGGCCTGTCGTAAGTTTTGTCGCGTTTACGGGGGACAGGGCAGGAGGAAGGAGGAGGCCGTCCCGCCGGAGACAAAGCCGTCCCGGGTGTTTCCTCATGGCCCCTTTTATACCCCAGCCGAGGACGCGTGCCTGGACTCCCCGCCCCCGGAGACCCCCAAACCTTCCCACACCACACCACCCGGCGATGCCGAGCGCCTGTGTCATCTGCAGGAGATCCTGGCCCAGATGTACGGAAACCAGGACTACCCCATAGAGGACGACCCCAGCGCGGATGCCGCGGACGATGTCGACGAGGACGCCCCGGACGACGTGGCCTATCCGGAGGAATACGCAGAGGAGCTTTTTCTGCCCGGGGACGCGACCGGTCCCCTTATCGGGGCCAACGACCACATCCCTCCCCCGCGTGGCGCATCTCCCCCCGGTATACGACGACGCAGCCGGGATGAGATTGGGGCCACGGGATTTACCGCAGAAGAGCTGGACGCCATGGACAGGCAGGCGGCTCGAGCCATCAGCCGCGGCGGCAAGCCCCCCTCGACCATGGCCAAGCTGGTGACTGGCATGGGCTTTACGATCCACGGAGCGCTCACCCCAGGATCGGAGGGGTGTGTCTTTGACAGCAGCCACCCAGATTACCCCCAACGGGTAATCGTGAAGGCGGGGTGGTACACGAGCACGAGCCACGAGGCGCGACTGCTGAGGCGACTGGACCACCCGGCGATCCTGCCCCTCCTGGACCTGCATGTCGTCTCCGGGGTCACGTGTCTGGTCCTCCCCAAGTACCAGGCCGACCTGTATACCTATCTGAGTAGGCGCCTGAACCCACTGGGACGCCCGCAGATCGCAGCGGTCTCCCGGCAGCTCCTAAGCGCCGTTGACTACATTCACCGCCAGGGCATTATCCACCGCGACATTAAGACCGAAAATATTTTTATTAACACCCCCGAGGACATTTGCCTGGGGGACTTTGGTGCCGCGTGCTTCGTGCAGGGTTCCCGATCAAGCCCCTTCCCCTACGGAATCGCCGGAACCATCGACACCAACGCCCCCGAGGTCCTGGCCGGGGATCCGTATACCACGACCGTCGACATTTGGAGCGCCGGTCTGGTGATCTTCGAGACTGCCGTCCACAACGCGTCCTTGTTCTCGGCCCCCCGCGGCCCCAAAAGGGGCCCGTGCGACAGTCAGATCACCCGCATCATCCGACAGGCCCAGGTCCACGTTGACGAGTTTTCCCCGCATCCAGAATCGCGCCTCACCTCGCGCTACCGCTCCCGCGCGGCCGGGAACAATCGCCCGCCTTACACCCGACCGGCCTGGACCCGCTACTACAAGATGGACATAGACGTCGAATATCTGGTTTGCAAAGCCCTCACCTTCGACGGCGCGCTTCGCCCCAGCGCCGCAGAGCTGCTTTGTTTGCCGCTGTTTCAACAGAAATGACCGCCCCCGGGGGGCGGTGCTGTTTGCGGGTTGGCACAAAAAGACCCCGACCCGCGTCTGTGGTGTTTTTGGCATCATGTCGCCGGGCGCCATGCGTGCCGTTGTTCCCATTATCCCATTCCTTTTGGTTCTTGTCGGTGTATCGGGGGTTCCCACCAACGTCTCCTCCACCACCCAACCCCAACTCCAGACCACCGGTCGTCCCTCGCATGAAGCCCCCAACATGACCCAGACCGGCACCACCGACTCTCCCACCGCCATCAGCCTTACCACGCCCGACCACACACCCCCCATGCCAAGTATCGGACTGGAGGAGGAGGAGGAAGAGGAGGAGGGGGCCGGGGATGGCGAACATCTTAAGGGGGGAGATGGGACCCGTGACACCCTACCCCAGTCCCCGGGTCCAGCCGTCCCGTTGGCCGGGGATGACGAGAAGGACAAACCCAACCGTCCCGTAGTCCCACCCCCCGGTCCCAACAACTCCCCCGCGCGCCCCGAGACCAGTCGACCGAAGACACCCCCCACCAGTATCGGGCCGCTGGCAACTCGACCCACGACCCAACTCCCCTCAAAGGGGCGACCCTTGGTTCCGACGCCTCAACATACCCCGCTGTTCTCGTTCCTCACTGCCTCCCCCGCCCTGGACACCCTCTTCGTCGTCAGCACCGTCATCCACACCTTATCGTTTGTGTGTATTGTTGCTATGGCGACACACCTGTGTGGTGGTTGGTCCAGACGCGGGCGACGCACACACCCTAGCGTGCGTTACGTGTGCCTGCCGCCCGAACGCGGGTAGGGTATGGGGCGGGGATGGGGAGAGCCCACACGCGGAAAGCAAGAACAATAAAGGCGGCGGGATCTAGTTGATATGCGTCTCTGGGTGTTTTTGGGGTGTGGTGGGCGCGGGGCGGTCATTGGACGGGGGTGCAGTTAAATACATGCCCGGGACCCATGAAGCATGCGCGACTTCCGGGCCTCGGAACCCACCCGAAACGGCCAACGGACGTCTGAGCCAGGCCTGGCTATCCGGAGAAACAGCACACGACTTGGCGTTCTGTGTGTCGCGATGTCTCTGCGCGCAGTCTGGCATCTGGGGCTTTTGGGAAGCCTCGTGGGGGCTGTTCTTGCCGCCACCCATCTGGGACCTGCGGCCAACACAACGGACCCCTTAACGCACGCCCCAGTGTCCCCTCACCCCAGCCCCCTGGGGGGCTTTGCCGTCCCCCTCGTAGTCGGTGGGCTGTGTGCCGTAGTCCTGGGGGCGGCGTGTCTGCTTGAGCTCCTGCGTCGTACGTGCCGCGGGTGGGGGCGTTACCATCCCTACATGGACCCAGTTGTCGTATAATTTTTTCCCCCCCCCCCCTTCTCCGCATGGGTGATGTCGGGTCCAAACTCCCGACACCACCAGCTGGCATGGTATAAATCACCGGTGCGCCCCCCAAACCATGTCCGGCAGGGGGATGGGGGGCGAATGCGGAGGGCACCCAACAACACCGGGCTAACCAGGAAATCCGTGGCCCCGGCCCCCAACAAAGATCGCGGTAGCCCGGCCGTGTGACATTATCGTCCATACCTACCACACCGACGAATCCCCTAAGGGGGAGGGGCCATTTTACGAGGAGGAGGGGTATAACAAAGTCTGTCTTTAAAAAGCAGGGGTTAGGGAGTTGTTCGGTCATAAGCTTCAGTGCGAACGACCAACTACCCCGATCATCAGTTATCCTTAAGGTCTCTTTTGTGTGGTGCGTTCCGGTATGGGGGGGGCTGCCGCCAGGTTGGGGGCCGTGATTTTGTTTGTCGTCATAGTGGGCCTCCATGGGGTCCGCGGCAAATATGCCTTGGCGGATGCCTCTCTCAAGATGGCCGACCCCAATCGCTTTCGCGGCAAAGACCTTCCGGTCCTGGACCAGCTGACCGACCCTCCGGGGGTCCGGCGCGTGTACCACATCCAGGCGGGCCTACCGGACCCGTTCCAGCCCCCCAGCCTCCCGATCACGGTTTACTACGCCGTGTTGGAGCGCGCCTGCCGCAGCGTGCTCCTAAACGCACCGTCGGAGGCCCCCCAGATTGTCCGCGGGGCCTCCGAAGACGTCCGGAAACAACCCTACAACCTGACCATCGCTTGGTTTCGGATGGGAGGCAACTGTGCTATCCCCATCACGGTCATGGAGTACACCGAATGCTCCTACAACAAGTCTCTGGGGGCCTGTCCCATCCGAACGCAGCCCCGCTGGAACTACTATGACAGCTTCAGCGCCGTCAGCGAGGATAACCTGGGGTTCCTGATGCACGCCCCCGCGTTTGAGACCGCCGGCACGTACCTGCGGCTCGTGAAGATAAACGACTGGACGGAGATTACACAGTTTATCCTGGAGCACCGAGCCAAGGGCTCCTGTAAGTACGCCCTCCCGCTGCGCATCCCCCCGTCAGCCTGCCTCTCCCCCCAGGCCTACCAGCAGGGGGTGACGGTGGACAGCATCGGGATGCTGCCCCGCTTCATCCCCGAGAACCAGCGCACCGTCGCCGTATACAGCTTGAAGATCGCCGGGTGGCACGGGCCCAAGGCCCCATACACGAGCACCCTGCTGCCCCCGGAGCTGTCCGAGACCCCCAACGCCACGCAGCCAGAACTCGCCCCGGAAGACCCCGAGGATTCGGCCCTCTTGGAGGACCCCGTGGGGACGGTGGCGCCGCAAATCCCACCAAACTGGCACATCCCGTCGATCCAGGACGCCGCGACGCCTTACCATCCCCCGGCCACCCCGAACAACATGGGCCTGATCGCCGGCGCGGTGGGCGGCAGTCTCCTGGCAGCCCTGGTCATTTGCGGAATTGTGTACTGGATGCACCGCCGCACTCGGAAAGCCCCAAAGCGCATACGCCTCCCCCACATCCGGGAAGACGACCAGCCGTCCTCGCACCAGCCCTTGTTTTACTAGATACCCCCCCCCTTAATGGGTGCGGGGGGGGTCAGGTCTGCGGGGTTGGGATGGGACCTTAACTCCATATAAAGCGAGTCTGGAAGGGGGGAAAGGCGGACAGTCGATAAGTCGGTAGCGGGGGACGCGCACCTGTTCCGCCTGTCGCACCCACAGCTTTTTCGCGAACCGTCCCGTTTCGGGATGCCGTGCCGCCCGTTGCAGGGCCTGGTGCTCGTGGGCCTCTGGGTCTGTGCCACCAGCCTGGTTGTCCGCCCCCCCCTTAATGGGTGCGGGGGGGGTCAGGTCTGCGGGGTTGGGATGGGACCTTAACTCCATATAAAGCGAGICTGGAAGGGGGGAAAGGCGGACAGTCGATAAGTCGGTAGCGGGGGACGCGCACCTGTTCCGCCTGTCGCACCCACAGCTTTTTCGCGAACCGTCCCGTTTCGGGATGCCGTGCCGCCCGTTGCAGGGCCTGGTGCTCGTGGGCCTCTGGGTCTGTGCCACCAGCCTGGTTGTCCGTGGCCCCACGGTCAGTCTGGTATCAAACTCATTTGTGGACGCCGGGGCCTTGGGGCCCGACGGCGTAGTGGAGGAAGACCTGCTTATTCTCGGGGAGCTTCGCTTTGTGGGGGACCAGGTCCCCCACACCACCTACTACGATGGGGTCGTAGAGCTGTGGCACTACCCCATGGGACACAAATGCCCACGGGTCGTGCATGTCGTCACGGTGACCGCGTGCCCACGTCGCCCCGCCGTGGCATTTGCCCTGTGTCGCGCGACCGACAGCACTCACAGCCCCGCATATCCCACCCTGGAGCTGAATCTGGCCCAACAGCCGCTTTTGCGGGTCCGGAGGGCGACGCGTGACTATGCCGGGGIGTACGTGTTACGCGTATGGGTCGGGGACGCACCAAACGCCAGCCTGTTTGTCCTGGGGATGGCCATAGCCGCCGAAGGTACTCTGGCGTACAACGGCTCGGCCCATGGCTCCTGCGCCCCGAAACTGCTTCCGTCTTCGGCCCCGCGTCTGGCCCCGGCGAGCGTATACCAACCCGCCCCTAACCCGGCCTCCACCCCCTCGACCACCACCTCCACCCCCTCGACCACCATCCCCGCTCCCCAAGCATCGACCACACCCTTCCCCACGGGAGACCCAAAACCCCAACCTCACGGGGTCAACCACGAACCCCCATCGAATGCCACGCGAGCGACCCGCGACTCGCGATATGCGCTAACGGTGACCCAGATAATCCAGATAGCCATCCCCGCGTCCATTATAGCCCTGGTGTTTCTGGGGAGCTGTATTTGCTTTATACACAGATGTCAACGCCGCTACCGACGCTCCCGCCGCCCGATTTACAGCCCCCAGATACCCACGGGCATCTCATGCGCGGTGAACGAAGCGGCCATGGCCCGCCTCGGAGCCGAGCTCAAATCGCATCCGAGCACCCCCCCCAAATCCCGGCGCCGGTCGTCACGCACGCCAATGCCCTCCCTGACGGCCATCGCCGAAGAGTCGGAGCCCGCGGGGGCGGCTGGGCTTCCGACGCCCCCCGTGGACCCCACGACATCCACCCCAACGCCTCCCCTGTTGGTATAGGTCCACGGCCACTGGCCGGGGGCACCACATAACCGACCGCAGTCACTGAGTTGGGAATAAACCGGTATTATTTACCTATATCCGTGTATGTCCATTTCTTTCTTCCCCCCCCCCCCGGAAACCAAAGAAGGAAGCAAAGAATGGATGGGAGGAGTTCAGGAAGCCGGGGAGAGGGCCCGCGGCGCATTTAAGGCGTTGTTGTGTTGACTTTGGCTCTTCTGGCGGGTTGGTGCGGTGCTGTTTGTTGGGCTCCCATTTTACCCGAAGATCGGCTGCTATCCCCGGGACATGGATCGCGGGGCGGTGGTGGGGTTTCTTCTCGGTGTTTGTGTTGTATCGTGCTTGGCGGGAACGCCCAAAACGTCCTGGAGACGGGTGAGTGTCGGCGAGGACGTTTCGTTGCTTCCAGCTCCGGGGCCTACGGGGCGCGGCCCGACCCAGAAACTACTATGGGCCGTGGAACCCCTGGATGGGTGCGGCCCCTTACACCCGTCGTGGGTCTCGCTGATGCCCCCCAAGCAGGTGCCCGAGACGGTCGTGGATGCGGCGTGCATGCGCGCTCCGGTCCCGCTGGCGATGGCGTACGCCCCCCCGGCCCCATCTGCGACCGGGGGTCTACGAACGGACTTCGTGTGGCAGGAGCGCGCGGCCGTGGTTAACCGGAGTCTGGTTATTCACGGGGTCCGAGAGACGGACAGCGGCCTGTATACCCTGTCCGTGGGCGACATAAAGGACCCGGCTCGCCAAGTGGCCTCGGTGGTCCTGGTGGTGCAACCGGCCCCAGTTCCGACCCCACCCCCGACCCCAGCCGATTACGACGAGGATGACAATGACGAGGGCGAGGACGAAAGTCTCGCCGGCACTCCCGCCAGCGGGACCCCCCGGCTCCCGCCTCCCCCCGCCCCCCCGAGGTCTTGGCCCAGCGCCCCCGAAGTCTCACATGTGCGTGGGGTGACCGTGCGTATGGAGACTCCGGAAGCTATCCTGTTTTCCCCCGGGGAGACGTTCAGCACGAACGTCTCCATCCATGCCATCGCCCACGACGACCAGACCTACTCCATGGACGTCGTCTGGTTGAGGTTCGACGTGCCGACCTCGTGTGCCGAGATGCGAATATACGAATCGTGTCTGTATCACCCGCAGCTCCCAGAATGTCTGTCCCCGGCCGACGCGCCGTGCGCCGCGAGTACGTGGACGTCTCGCCTGGCCGTCCGCAGCTACGCGGGGTGTTCCAGAACAAACCCCCCACCGCGCTGTTCGGCCGAGGCTCACATGGAGCCCGTCCCGGGGCTGGCGTGGCAGGCGGCCTCCGTCAATCTGGAGTTCCGGGACGCGTCCCCACAACACTCCGGCCTGTATCTGTGTGTGGTGTACGTCAACGACCATATTCACGCCTGGGGCCACATTACCATCAGCACCGCGGCGCAGTACCGGAACGCGGTGGTGGAACAGCCCCTCCCACAGCGCGGCGCGGATTTGGCCGAGCCCACCCACCCGCACGTCGGGGCCCCTCCCCACGCGCCCCCAACCCACGGCGCCCTGCGGTTAGGGGCGGTGATGGGGGCCGCCCTGCTGCTGTCTGCGCTGGGGTTGTCGGTGTGGGCGTGTATGACCTGTTGGCGCAGGCGTGCCTGGCGGGCGGTTAAAAGCAGGGCCTCGGGTAAGGGGCCCACGTACATTCGCGTGGCCGACAGCGAGCTGTACGCGGACTGGAGCTCGGACAGCGAGGGAGAACGCGACCAGGTCCCGTGGCTGGCCCCCCCGGAGAGACCCGACTCTCCCTCCACCAATGGATCCGGCTTTGAGATCTTATCACCAACGGCTCCGTCTGTATACCCCCGTAGCGACGGGCATCAATCTCGCCGCCAGCTCACAACCTTTGGATCCGGAAGGCCCGATCGCCGTTACTCCCAGGCCTCCGATTCGTCCGTCTTCTGGTAAGGCGCCCCATCCCGAGGCCCCACGTCGGTCGCCGAACTGGGCGACCGCCGGCGAGGTGGACGTCGGAGACGAGCTAATCGCGATTTCCGACGAACGCGGACCCCCCCGACATGACCGCCCGCCCCTCGCCACGTCGACCGCGCCCTCGCCACACCCGCGACCCCCGGGCTACACGGCCGTTGTCTCCCCGATGGCCCTCCAGGCTGTCGACGCCCCCTCCCTGTTTGTCGCCTGGCTGGCCGCTCGGTGGCTCCGGGGGGCTTCCGGCCTGGGGGCCGTCCTGTGTGGGATTGCGTGGTATGTGACGTCAATTGCCCGAGGCGCACAAAGGGCCGGTGGTCCGCCTAGCCGCAGCAAATTAAAAATCGTGAGTCACAGCGACCGCAACTTCCCACCCGGAGCTTTCTTCCGGCCTCGATGACGTCCCGGCTCTCCGATCCCAACTCCTCAGCGCGATCCGACATGTCCGTGCCGCTTTATCCCACGGCCTCGCCAGTTTCGGTCGAAGCCTACTACTCGGAAAGCGAAGACGAGGCGGCCAACGACTTCCTCGTACGCATGGGCCGCCAACAGTCGGTATTAAGGCGTTGACGCAGACGCACCCGCTGCGTCGGCATGGTGATCGCCTGTCTCCTCGTGGCCGTTCTGTCGGGCGGATTTGGGGCGCTCCTGATGTGGCTGCTCCGCTAAAAGACCGCATCGACACGCGCGTCCTTCTTGTCGTCTCTCTTCCCCCCCATCACCCCGCAATTTGCACCCAGCCTTTAACTACATTAAATTGGGTTCGATTGGCAATGTTGTCTCCCGGTTGATTTTTGGGTGGGTGGGGAGTGGGTGGGTGGGGAGTGGSEQ ID NO: 9 is a nucleotide sequence that encodes pSH-tetR.(SEQ ID NO: 9)tcgcgcgtttcggtgatgacggtgaaaacctctgacacatgcagctcccggagacggtcacagcttgtctgtaagcggatgccgggagcagacaagcccgtcagggcgcgtcagcgggtgttggcgggtgtcggggctggcttaactatgcggcatcagagcagattgtactgagagtgcaccatatgcggtgtgaaataccgcacagatgcgtaaggagaaaataccgcatcaggcgccattcgccattcaggctgcgcaactgttgggaagggcgatcggtgcgggcctcttcgctattacgccagctggcgaaagggggatgtgctgcaaggcgattaagttgggtaacgccagggttttcccagtcacgacgttgtaaaacgacggccagtgccaagcttggctgcaggtcaacaccagagcctgcccaacatggcacccccactcccacgcacccccactcccacgcacccccactcccacgcacccccactcccacgcacccccactcccacgcacccccactcccacgcacccccactcccacgcacccccactcccacgcacccccactcccacgcatccccgcgatacatccaacacagacagggaaaagatacaaaagtaaacctttatttcccaacagacagcaaaaatcccctgagtttttttttattagggccaacacaaaagacccgctggtgtgtggtgcccgtgtctttcacttttcccctccccgacacggattggctggtgtagtgggcgcggccagagaccacccagcgcccgacccccccctccccacaaacacggggggcgtcccttattgttttccctcgtcccgggtcgaccagacatgataagatacattgatgagtttggacaaaccacaactagaatgcagtgaaaaaaatgctttatttgtgaaatttgtgatgctattgctttatttgtaaccattataagctgcaataaacaagttctgctttaataagatctgaattcccgggatccgctgtacgcggacccactttcacatttaagttgtttttctaatccgcatatgatcaattcaaggccgaataagaaggctggctctgcaccttggtgatcaaataattcgatagcttgtcgtaataatggcggcatactatcagtagtaggtgtttccctttcttctttagcgacttgatgctcttgatcttccaatacgcaacctaaagtaaaatgccccacagcgctgagtgcatataatgcattctctagtgaaaaaccttgttggcataaaaaggctaattgattttcgagagtttcatactgtttttctgtaggccgtgtacctaaatgtacttttgctccatcgcgatgacttagtaaagcacatctaaaacttttagcgttattacgtaaaaaatcttgccagctttccccttctaaagggcaaaagtgagtatggtgcctatctaacatctcaatggctaaggcgtcgagcaaagcccgcttattttttacatgccaatacaatgtaggctgctctacacctagcttctgggcgagtttacgggttgttaaaccttcgattccgacctcattaagcagctctaatgcgctgttaatcactttacttttatctaatctagacatatcaattcgccctatagtgagtcgtattacaattctttgccaaaatgatgagacagcacaataaccagcacgttgcccaggagctgtaggaaaaagaagaaggcatgaacatggttagcagaggggcccggtttggactcagagtattttatcctcatctcaaacagtgtatatcattgtaaccataaagagaaaggcaggatgatgaccaggatgtagttgtttctaccaataagaatatttccacgccagccagaatttatatgcagaaatattctaccttatcatttaattataacaattgttctctaaaactgtgctgaagtacaatataatataccctgattgccttgaaaaaaaagtgattagagaaagtacttacaatctgacaaataaacaaaagtgaatttaaaaattcgttacaaatgcaagctaaagtttaacgaaaaagttacagaaaatgaaaagaaaataagaggagacaatggttgtcaacagagtagaaagtgaaagaaacaaaattatcatgagggtccatggtgatacaagggacatcttcccattctaaacaacaccctgaaaactttgccccctccatataacatgaattttacaatagcgaaaaagaaagaacaatcaagggtccccaaactcaccctgaagttctcaggatcgatccggagctttttgcaaaagcctaggcctccaaaaaagcctcttcactacttctggaatagctcagaggccctagaggatccccggcggggtcgtatgcggctggagggtcgcggacggagggtccctgggggtcgcaacgtaggcggggcttctgtggtgatgcggagagggggcggcccgagtctgcctggctgctgcgtctcgctccgagtgccgaggtgcaaatgcgaccagactgtcgggccagggctaacttataccccacgcctttcccctccccaaaggggcggcagtgacgattcccccaatggccgcgcgtcccaggggaggcaggcccaccgcggggcggccccgtccccggggaccaacccggcgcccccaaagaatatcattagcatgcacggcccggcccccgatttgggggcccaacccggtgtcccccaaagaaccccattagcatgcccctcccgccgacgcaacaggggcttggcctgcgtcggtgccccggggcttcccgccttcccgaagaaactcattaccatacccggaaccccaggggaccaatgcgggttcattgagcgacccgcgggccaatgcgcgaggggccgtgtgttccgccaaaaaagcaattagcataacccggaaccccaggggagtggttacgcgcggcgcgggaggcggggaataccggggttgcccattaagggccgcgggaattgccggaagcgggaagggcggccggggccgcccattaatgagtttctaattaccataccgggaagcggaacaaggcctcttgcaagtttttaattaccataccgggaagtgggcggcccggcccattgggcggtaactcccgcccaatgggccgggccccgaagactcggcggacgctggttggccgggccccgccgcgctggcggccgccgattggccagtcccgcccccgaggcggcccgccctgtgagggcgggctggctccaagcgtatatatgcgcggctcctgccatcgtctctccggagagcggcttggtgcggagctcgaattcggtaatcatggtcatagctgtttcctgtgtgaaattgttatccgctcacaattccacacaacatacgagccggaagcataaagtgtaaagcctggggtgcctaatgagtgagctaactcacattaattgcgttgcgctcactgcccgctttccagtcgggaaacctgtcgtgccagctgcattaatgaatcggccaacgcgcggggagaggcggtttgcgtattgggcgctcttccgcttcctcgctcactgactcgctgcgctcggtcgttcggctgcggcgagcggtatcagctcactcaaaggcggtaatacggttatccacagaatcaggggataacgcaggaaagaacatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgtttccccctggaagctccctcgtgcgctctcctgttccgaccctgccgcttaccggatacctgtccgcctttctcccttcgggaagcgtggcgctttctcaatgctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtcttgagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaaggacagtatttggtatctgcgctctgctgaagccagttaccttcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacggggtctgacgctcagtggaacgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctcagcgatctgtctatttcgttcatccatagttgcctgactccccgtcgtgtagataactacgatacgggagggcttaccatctggccccagtgctgcaatgataccgcgagacccacgctcaccggctccagatttatcagcaataaaccagccagccggaagggccgagcgcagaagtggtcctgcaactttatccgcctccatccagtctattaattgttgccgggaagctagagtaagtagttcgccagttaatagtttgcgcaacgttgttgccattgctacaggcatcgtggtgtcacgctcgtcgtttggtatggcttcattcagctccggttcccaacgatcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggttagctccttcggtcctccgatcgttgtcagaagtaagttggccgcagtgttatcactcatggttatggcagcactgcataattctcttactgtcatgccatccgtaagatgcttttctgtgactggtgagtactcaaccaagtcattctgagaatagtgtatgcggcgaccgagttgctcttgcccggcgtcaatacgggataataccgcgccacatagcagaactttaaaagtgctcatcattggaaaacgttcttcggggcgaaaactctcaaggatcttaccgctgttgagatccagttcgatgtaacccactcgtgcacccaactgatcttcagcatcttttactttcaccagcgtttctgggtgagcaaaaacaggaaggcaaaatgccgcaaaaaagggaataagggcgacacggaaatgttgaatactcatactcttcctttttcaatattattgaagcatttatcagggttattgtctcatgagcggatacatatttgaatgtatttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgccacctgacgtctaagaaaccattattatcatgacattaacctataaaaataggcgtatcacgaggccctttcgtcSEQ ID NO: 10 is a nucleotide sequence that encodes the open reading frame ofgK (strain KOS). (SEQ ID NO: 10)atgctcgccg tccgttccct gcagcacctc tcaaccgtcg tcttgataac ggcgtacggc ctcgtgctcgtgtggtacac cgtcttcggt gccagtccgc tgcaccgatg tatttacgcg gtacgcccca ccggcaccaacaacgacacc gccctcgtgt ggatgaaaat gaaccagacc ctattgtttc tgggggcccc gacgcacccccccaacgggg gctggcgcaa ccacgcccat atctgctacg ccaatcttat cgcgggtagg gtcgtgcccttccaggtccc acccgacgcc acgaatcgtc ggatcatgaa cgtccacgag gcagttaact gtctggagaccctatggtac acacgggtgc gtctggtggt cgtagggtgg ttcctgtatc tggcgttcgt cgccctccaccaacgccgat gtatgtttgg tgtcgtgagt cccgcccaca agatggtggc cccggccacc tacctcttgaactacgcagg ccgcatcgta tcgagcgtgt tcctgcagta cccctacacg aaaattaccc gcctgctctgcgagctgtcg gtccagcggc aaaacctggt tcagttgttt gagacggacc cggtcacctt cttgtaccaccgccccgcca tcggggtcat cgtaggctgc gagttgatgc tacgctttgt ggccgtgggt ctcatcgtcggcaccgcttt catatcccgg ggggcatgtg cgatcacata ccccctgttt ctgaccatca ccacctggtgttttgtctcc accatcggcc tgacagagct gtattgtatt ctgcggcggg gcccggcccc caagaacgcagacaaggccg ccgccccggg gcgatccaag gggctgtcgg gcgtctgcgg gcgctgttgt tccatcatcctgtcgggcat cgcaatgcga ttgtgttata tcgccgtggt ggccggggtg gtgctcgtgg cgcttcactacgagcaggag atccagaggc gcctgtttga tgtatga

1. An oncolytic Herpes Simplex Virus (HSV) comprising recombinant DNA,wherein the recombinant DNA comprises: a) a gene comprising a 5′untranslated region and a HSV-1, or HSV-2, VP5 gene that is operablylinked to an VP5 promoter comprising a TATA element; b) a tetracyclineoperator sequence positioned between 6 and 24 nucleotides 3′ to saidTATA element, wherein the VP5 gene lies 3′ to said tetracycline operatorsequence; c) a gene sequence encoding tetracycline repressor operablylinked to an HSV immediate-early promoter, wherein the gene sequence islocated at the ICP0 locus; d) a variant gene that increases syncytiumformation as compared to wild type, wherein the HSV-1, or HSV-2, variantgene is selected from the group consisting of: a glycoprotein K (gK)variant; a glycoprotein B (gB) variant; a UL24 variant; and UL20 genevariant; and e) a gene sequence encoding a functional ICP34.5 protein;wherein said oncolytic HSV does not encode functional ICP0 and does notcontain a ribozyme sequence located in said 5′ untranslated region ofVP5.
 2. The oncolytic HSV of claim 1, wherein the variant gene is a gKvariant gene that encodes an amino acid substitution selected from thegroup consisting of: an Ala to Thr amino acid substitution correspondingto amino acid 40 of SEQ ID NO: 2; an Ala to “x” amino acid substitutioncorresponding to amino acid 40 of SEQ ID NO: 2, wherein “x” is any aminoacid; an Asp to Asn amino acid substitution corresponding to amino acid99 of SEQ ID NO: 2; a Leu to Pro amino acid substitution correspondingto amino acid 304 of SEQ ID NO: 2; and an Arg to Leu amino acidsubstitution corresponding to amino acid 310 of SEQ ID NO:
 2. 3. Theoncolytic HSV of any of claims 1-2, wherein the tetracycline operatorsequence comprises two Op2 repressor binding sites.
 4. The oncolytic HSVof any of claims 1-3, wherein the VP5 promoter is an HSV-1 or HSV-2 VP5promoter.
 5. The oncolytic HSV of any of claims 1-4, wherein theimmediate-early promoter is an HSV-1 or HSV-2 immediate-early promoter.6. The oncolytic HSV of any of claims 1-5, wherein the HSVimmediate-early promoter is selected from the group consisting of: ICP0promoter and ICP4 promoter.
 7. The oncolytic HSV of any of claims 1-6,wherein the recombinant DNA is part of the HSV-1 genome.
 8. Theoncolytic HSV of any of claims 1-6, wherein the recombinant DNA is partof the HSV-2 genome.
 9. The oncolytic HSV of any of claims 1-8, furthercomprising a pharmaceutically acceptable carrier.
 10. The oncolytic HSVof any of claims 1-9, further encoding at least one polypeptide that canincrease the efficacy of the oncolytic HSV to induce ananti-tumor-specific immunity.
 11. The oncolytic HSV of claim 10, whereinthe at least one polypeptide encodes a product selected from the groupconsisting of: interleukin 2 (IL2), interleukin 12 (IL12), interleukin15 (IL15), an anti-PD-1 antibody or antibody reagent, an anti-PD-L1antibody or antibody reagent, an anti-OX40 antibody or antibody reagent,a CTLA-4 antibody or antibody reagent, a TIM-3 antibody or antibodyreagent, a TIGIT antibody or antibody reagent, a soluble interleukin 10receptor (IL10R), a fusion polypeptide between a soluble IL10R andIgG-Fc domain, a soluble TGFβ type II receptor (TGFBRII), a fusionpolypeptide between a soluble TGFBRII and IgG-Fc domain, an anti-IL10Rantibody or antibody reagent, an anti-IL10 antibody or antibody reagent,an anti-TGFBRII antibody or antibody reagent, and an anti-TGFBRIIantibody or antibody reagent.
 12. The oncolytic HSV of any of claims1-11, wherein the oncolytic HSV the further encodes fusogenic activity.13. A composition comprising an oncolytic HSV of any of claims 1-12. 14.The composition of claim 13, further comprising a pharmaceuticallyacceptable carrier.
 15. A method for treating cancer, the methodcomprising administering the oncolytic HSV of any of claims 1-12 or thecomposition of any of claims 13-14 to a subject having cancer.
 16. Themethod of claim 15, wherein the cancer is a solid tumor.
 17. The methodof claim 16, wherein the tumor is benign or malignant.
 18. The method ofany of claims 15-17, wherein the subject is diagnosed or has beendiagnosed as having cancer is selected from the list consisting of: acarcinoma, a melanoma, a sarcoma, a germ cell tumor, and a blastoma. 19.The method of any of claims 15-17, wherein the subject is diagnosed orhas been diagnosed as having a cancer selected from the group consistingof: non-small-cell lung cancer, breast cancer, brain cancer, coloncancer, prostate cancer, liver cancer, lung cancer, ovarian cancer, skincancer, head and neck cancer, kidney cancer, and pancreatic cancer. 20.The method of any of claims 15-19, wherein the cancer is metastatic. 21.The method of any of claims 15-19, further comprising administering anagent that regulates the tet operator-containing promoter.
 22. Themethod of claim 21, wherein the agent is doxycycline or tetracycline.23. The method of claim 21, wherein the agent is administered locally orsystemically.
 24. The method of claim 23, wherein the systemicadministration is oral administration.
 25. The method of any of claims15-23, wherein the oncolytic virus is administered directly to thetumor.
 26. An oncolytic Herpes Simplex Virus (HSV) comprisingrecombinant DNA, wherein the recombinant DNA does not encode functionalICP0; and encodes fusogenic activity.